In July 2000, Howard Stern, the morning host at Infinity's WXRK, got the company to issue a gag order on their other personalities, preventing them, including Hughes and Cumia, from talking about Stern or other Infinity hosts. Three months earlier, Stern threatened management with his resignation if they did not go through with his request, after Hughes and Cumia blew the news of a surprise rock concert that Stern was to announce the following morning. Stern called Hughes and Cumia "imitators" who were "dying to get some attention from me".[46] In 2004, Hughes revealed a stipulation in their Infinity contract that fined Cumia and himself $100,000 if they talked about other Infinity radio personalities.[47] In 2006, Stern admitted to the gag order: "When I'm in business with a company and they hire Howard Stern imitators to go on in the afternoon... I don't want anyone knocking me ... I turned to Mel Karmazin ... 'Your two boys that you hired, who sound identical to me ... they're gonna go insane. Watch.'" Hughes and Cumia claim the feud was started by Stern, adding that he "saw there was potential for 'The Opie & Anthony Show' to get an audience and perceived it as some kind of threat."[48]

In February 2001, Hughes and Cumia began to host XFL Gameday, the pre-game show for Vince McMahon's startup American football league, the XFL, produced by NBC and aired in New York City. The show, taped weekly at the WWF restaurant in Times Square, featured analysis by sportscaster Bruce Beck and football coach Rusty Tillman and risque content; one such segment featured Hughes and Cumia as chefs inserting a cucumber in between two melons. The show was cancelled after four weeks; McMahon stated that he had no creative control, adding: "I heard it was horrible. Had I seen it, I would have shut it down."[49]

By mid-2001, Opie and Anthony ranked first place in New York City in the 18-plus demographic.[50] Among their success came the announcement in June 2001, following what Hughes described as a "tug of war" period of discussions with Infinity and competing radio network Greater Media,[51] that he and Cumia had renewed their contracts with Infinity to continue on WNEW. As part of their new deal, the show entered national syndication to 22 Infinity-owned stations.[30] By the end of July 2001, the show aired in a total of nine cities,[52] and returned to Boston in August on WBCN, a long time rival of their former station WAAF.[50][53] By mid-August 2002, the number of affiliates had risen to 17.[54] Infinity took the show and the afternoon drive team of Don & Mike from WJFK-FM in Washington, D.C., off the air for two days in May 2002 following comments from both shows about their feud.[55]

In June 2002, the FCC issued a $21,000 fine to Infinity broadcasting for the broadcast of content from Opie and Anthony it deemed in breach of its indecency regulations, following listener complaints. The cited segments included the November 15, 2000 airing of "Teen Week", a song that detailed incestual sex between a father and daughter, a November 16, 2000 segment of "Guess What's in My Pants" which involved a sexual discussion with a seventeen-year-old female, and a song parody played on January 8, 2001, titled "I'm Horny for Little Girls".[56]

On July 13, 2002, Hughes, Cumia and Norton hosted the T&A with O&A beach party in Angola, New York attended by an estimated 5,000 people. The event featured stripping contests, a volleyball tournament among nightclub dancers, which developed into "a rowdy event combining full nudity and lewd acts with foreign objects". The event was investigated by the police, who arrested drunk drivers and attendees for disorderly conduct.[57]

Following their firing, Infinity competitor Clear Channel Communications wished to hire Hughes and Cumia to host mornings on one of their stations.[67] However, rather than release the pair from their contract, Infinity continued to pay them until their deals expired in June 2004 to prevent them broadcasting on another network.[68][69] Despite their efforts to get out of their contracts, Hughes and Cumia remained off the air for two years, remaining largely out of the public eye apart from odd appearances.[70] Both found the hiatus frustrating as they wished to broadcast and comment on the news and current events but had no outlet or an audience.[71] In January 2003, the show's remaining support staff were fired from WNEW,[72] and the station switched formats from talk to music.[73] In June, Hughes and Cumia were spotted visiting the offices of Sirius Satellite Radio for a meeting with their agent.[74] Hughes later claimed the WNEW years as the show's "golden age".[75]

On August 22, 2002, the show was suspended following its third annual Sex for Sam contest held on August 15 that encouraged listeners to have sex in risky places for prizes while a witness reported from the location.[58] Its name derived from the Boston Beer Company, producer of Samuel Adams beer that sponsored the contest and prize.[59] In the segment, comedian Paul Mecurio, on a cellphone, described Brian Florence and Loretta Harper, a Virginia couple visiting Manhattan, having simulated sex in a vestibule at St. Patrick's Cathedral, several feet away from a Mass service. The couple were arrested for public lewdness, and Mecurio for acting in concert.[58] The incident received widespread media attention, causing WNEW to issue an apology the following day, but it was rejected by the Catholic League that wrote to the FCC demanding Hughes and Cumia be fined and the removal of WNEW's license.[58] The Boston Beer Company also apologized.[60] The show aired live on the following day, but the hosts could not address the incident for legal reasons. WNEW aired a week of reruns while Infinity kept Hughes and Cumia off the air while the matter was reviewed. They were fired on August 22, in addition to WNEW's general manager and program director the day before.[54] Florence died from a heart attack in September 2003 and Harper and Mecurio pleaded guilty to disorderly conduct in 2003.[61]

The incident attracted 523 e-mail complaints sent to the FCC which launched an investigation.[62][63] In October 2003, Infinity received a $357,500 fine which marked the first time a fine was totalled by issuing $27,500 for each station that aired the offending content and not the station cited in a complaint.[64][65] As a result, the Catholic League dropped its bid to rescind WNEW's license.[66] Infinity appealed both fines issued in 2002 until Viacom, its parent company, agreed to a $3.5 million settlement in 2004 which cancelled all pending indecency violations against the broadcaster.[62]

In the first week of October 2010, Hughes and Cumia renewed their contract with SiriusXM to continue their radio show for an additional two years. They expressed disappointment with their new deal; Hughes described it as "mediocre", noting the company "got all their points, we got nothing".[106] On October 13, 2011, The ViRUS was relaunched as The Opie and Anthony Channel. The pair renewed their contracts in October 2012.[107] In April 2014, Hughes and Cumia celebrated the show's twentieth anniversary with a special live edition of the Unmasked radio comedy series at Carolines on Broadway comedy club, hosted by Ron Bennington.[108]

On July 3, 2014, SiriusXM fired Cumia for a series of tweets which they claimed were "racially-charged and hate-filled", following his alleged off air incident with a black woman on the street whereby Cumia was punched by her after he attempted to take a picture in Times Square, and he referred to black people as "savage, violent animals".[109][110][111] Cumia refused to apologize for his tweets,[112] and gave his blessing for Hughes and Norton to continue broadcasting as their contracts with Sirius remained intact.[113] Cumia deleted the tweets after being fired.[113] On July 14, the show was relaunched as Opie with Jim Norton and the channel was renamed SiriusXM Talk.[114] In October 2014, Hughes and Norton renewed their contracts for two more years,[115] and the channel was re-branded once more to Opie Radio.

In 2015, Hughes and Cumia were involved in a public feud on Twitter regarding their growing strained relationship over the years. The two expressed a wish to never work together again. In October 2016, growing differences between Hughes and Norton led to Hughes hosting afternoons with The Opie Radio Show and Norton staying in mornings on Jim Norton & Sam Roberts with former Opie and Anthony producer Sam Roberts. On October 4, the first day of Hughes's new afternoon show, Hughes and Cumia spoke for the first time in over two years in a phone call that was broadcast live during both of their respective shows. They have since had a number of on-air calls together.

On July 6, 2017, Hughes was fired from SiriusXM. His departure was based on an alleged incident where he filmed a colleague using the bathroom.