In 2003, Ghostface signed with Def Jam Records. After temporarily dropping "Killah" from his stage name, Ghostface released The Pretty Toney Album in April 2004. The album, while containing two RZA productions, featured none of the Clan; instead, it featured collaborations with Missy Elliott, D-Block and Jacki-O. The singles "Tush" and "Run", the collaborations with Missy and Jadakiss respectively, achieved moderate success in the clubs and charts, and the album was featured on numerous "best of the year" lists, including number nine on Pitchfork Media's. Ghostface also appeared on the track "On My Knees" by UK R&B group The 411, which became a hit in the UK and Australia, and released an album titled 718 (after the Staten Island area code) with a group of his protégés, the Theodore Unit. Ghostface also appeared on "He Comes" by De La Soul, on The Grind Date. In November 2005, Ghostface and Theodore Unit's breakout star Trife Da God released a joint project, Put It On The Line.
In 2006, Ghostface teamed up with underground artist MF Doom for a still unreleased album entitled Swift & Changeable. MF Doom also produced several songs for Ghostface's 2006 album Fishscale, which was once again attributed to "Ghostface Killah". The album debuted strongly, in the #4 position on the U.S. Billboard 200 and at #2 on the R&B charts, the rapper's most auspicious chart showing since the heyday of the Wu-Tang Clan and the release of his solo debut. The album also nearly unanimously received positive reviews. Ghostface embarked on a limited-date tour of US venues in support of the album, performing several of his concerts together with most members of the Wu-Tang Clan. On December 4, 2007, Ghostface released his seventh solo studio album, The Big Doe Rehab.
In a May 2008 interview, Ghostface Killah stated that he would make an R&B-inspired album in the vein of tracks he had done before with artists such as Ne-Yo and Jodeci. That album would become his eighth studio album Ghostdini: Wizard of Poetry in Emerald City to good reviews. It featured singles such as "Baby" and "Do Over". In March 2009, Ghostface also recorded a song called "Message from Ghostface" dedicated to women who were abused in relationships after the Rihanna/Chris Brown controversy.
Raekwon, in a May 2009 interview with Rolling Stone indicated that Ghostface Killah is preparing to release a new album. In response to a question asking if the Wu-Tang Clan are going to release a follow up to 8 Diagrams, Raekwon stated "Everybody's doing different things right now — you got Meth [Method Man] coming out with an album, you got Ghostface coming out with an album, some guys working on their projects, some guys getting into the film world, everybody is multi-tasking right now." Ghostface appeared on a total of 8 songs on Raekwon's highly anticipated release of Only Built 4 Cuban Linx... Pt. II.
Shortly after the release of Only Built 4 Cuban Linx... Pt. II, Def Jam contracted Raekwon to work with their label artists Method Man and Ghostface Killah on an album later titled Wu-Massacre. Production began in November 2009. Wu-Massacre was released March 30, 2010 to generally positive reviews from most music critics with some mixed criticism due to the album's rushed feel clocking in at a mere 30 minutes of music. With heavy promotion, it sold 37,900 units in its first week. It has sold 64,000 units as of May 12, 2010. It features production from Scram Jones, Mathematics, and the RZA who produced the album's lead single, "Our Dreams". Recently he confirmed that he will be releasing 2 studio albums with the first one out near December called Apollo Kids & releasing a sequel to his 2000 album Supreme Clientele. In 2011, Ghostface Killah featured on UK artist Josh Osho's debut single 'Redemption Days'.