As the projected release date started to draw in, speculation on the title of the band's debut album began to circulate. At first, it was believed that the album would be called "A Little Death Makes Life More Meaningful," which was later revealed to be a lyrics from the song "Little Death." Hoppus finally settled on "When Your Heart Stops Beating". A song, entitled "Lycanthrope" was released on the +44 website in early September 2006. This was only the second song that fans had heard other than "No, It Isn't" and had more of a "punk" feel to it.

Later in September 2006, KROQ radio played the title track of the forthcoming album after a message from Mark Hoppus through his User ImageMySpace blog, alerting fans to this fact. The band played their first gig on the September 7, 2006 at The Roxy Theatre in Hollywood; Hoppus stated it was the first show he had performed in two years. The band, followed this up by their second ever gig and first ever UK gig in London at the Astoria. Both gigs were met with very encouraging reactions from fans, considering that at that time, only one completely recorded and mastered song, "When Your Heart Stops Beating" had been heard.

A music video for "When Your Heart Stops Beating" was shot in a factory in LA shortly after their first gig. Fans were invited along to feature in the video if they were over the age of 18. The video debuted in the US on TRL in late September 2006. During the shooting of the video, Travis Barker injured his arm, which was discovered weeks later after playing a whole European promo tour. Fans can hear parts of this through Mark's podcast, Hi My Name Is Mark. This left the band with no option but to postpone part of its US tour, originally scheduled for October 2006, to December of the same year.

The album was released on November 14, 2006 in North America, November 13, 2006 in Europe, and November 11, 2006 in Australia. The band released two singles to support the album release; "When Your Heart Stops Beating" was released in the US whereas in the UK, "Lycanthrope" was released as a 7" vinyl on November 8, 2006.

Regarding the lyrical content of the album, Hoppus stated that "the +44 album is by far the most lyrically personal music I have ever written. The words are everything I have inside me put on a CD. This is the most personal album any of us have ever written. You want to know who we are, what we think, or how we feel? Listen to the +44 CD." The album refers to the break-up of blink-182, and "the ugly feelings that were left over afterwards," according to Hoppus. The song "No It Isn't", released on Tom Delonge's birthday, December 13, is primarily directed towards DeLonge's departure from blink-182.

The band appeared on The Late Show with David Letterman on November 15, 2006, playing "When Your Heart Stops Beating", as well as Jimmy Kimmel Live on December 19, 2006.

+44 did a cover of the Descendents' song, "Christmas Vacation" for KROQ's Kevin & Bean's Christmas album, and on tour in Minneapolis, Minnesota, at First Avenue. Later they did a cover of Berlin's song, The Metro, for their second European Tour. They also covered Black Flag's Nervous Breakdown on their Japan tour. All vocals were sang by Craig. They have recorded a cover of The Smashing Pumpkins' I Am One. This will be on The Smashing Pumpkins' tribute album only available in July 2007's SPIN magazine.

+44's When Your Heart Stops Beating was ranked number 2 in Maxim's top 10 music for 2006.

The second UK single is "When Your Heart Stops Beating" to coincide with their tour in Europe. It was released on February 12, 2007. It was released on 7" vinyl containing the title track and an electronic mix of the title track. The CD version contains the title track and "Baby Come On". The second planned single in the USA was "Baby Come On" according to Mark Hoppus' blog, http://himynameismark.com/. A promotional cd was released for the song in the US, however 155 has been confirmed as the next USA single.