This song, like Phil Collins' solo track "I Missed Again" (recorded at around the same time), makes prominent use of a horn section, arranged by Tom Tom 84 (i.e. Thomas Washington, horn arranger for Earth, Wind & Fire) and played by that band's wind players, credited on the song as "EWF Horns". The song marks a step toward the mainstream pop direction Genesis was taking at the time, yet it still contains elements of their past: complex, melodic bass riffs, and a cross-hand technique on a Prophet-5, similar to the style used for the intro to "The Lamb Lies Down on Broadway."

The song was critically unsuccessful. When Genesis performed the song live during a concert in Leiden, the Netherlands, on 3 October 1981, the band was booed. The song's lack of popularity lead to it being excluded from the Platinum Collection and the setlist for their 2007 tour.

The song was released as the first single from Abacab in the U.S., and reached the U.S. Top 30 in the fall of 1981. "No Reply at All" spent 18 weeks on the Billboard Hot 100, longer than most of their hits which reached the Top 10, including "Invisible Touch", which spent only 17 weeks on the chart.

The song was performed live by Phish as a tribute to Genesis at the Rock and Roll Hall of Fame's 2010 induction ceremony. Phish also performed "Watcher of the Skies" that night. Tony Banks and Phil Collins would later state during the ceremony that the song was not any good live.

When introducing the song on the 1981 Abacab tour, Collins said it is about miscommunication between two people in a relationship.

The music video features only the band. Cameras revolve around the band playing their parts in a rehearsal setting. When the horn part is prominent, it cuts to a different shot of the band – wearing hats, sunglasses, and jackets to conceal their identity – playing the trumpet, saxophone and trombone.

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