After visiting the United States during a live stint with the Immaculate Consumptive (Lydia Lunch, Nick Cave and Marc Almond) Thirlwell settled in New York City, where he is still based.

Since 2000, Thirlwell has become more active as a composer, having written commissions for Bang on a Can, League of Electronic Musical Urban Robots, and the Kronos Quartet, and scoring cartoons The Venture Bros. for Adult Swim and Archer for FX.

Thirlwell's music—released under his various project names of Foetus, Wiseblood, Steroid Maximus, Baby Zizanie, Manorexia and others—includes elements of 20th-century classical music, noise, big band, Americana, jazz, punk rock, African and Cuban percussion, and epic/horror film soundtracks.

Recurring lyrical themes include destruction, persecution, anxiety, abuse, incest, masochism, angst, self-destruction, self-abuse, lust, prejudice, murder, failure and machismo, often expressed using American colloquialism and black humour.

Furthering the confusion, Thirlwell adopted these personas outside of his own recordings; for example, Frank Want can be found on The The's Soul Mining and on releases by Orange Juice, with whom he appeared on Top of the Pops.

Ruin is also credited on numerous releases for a variety of roles with Boss Hog, Coil, Fur Bible, Annie Hogan, Nurse With Wound, Pigface, Sonic Youth, Workdogs and others.