She hosted the first episode of the reality TV show On the Lot, but quit before the second episode aired, saying later that she left, "Because I smelled the disaster happening before it did." The show, produced by Steven Spielberg and Mark Burnett, was a competition for aspiring filmmakers vying for a chance at stardom. Handler was replaced by former Robin & Company entertainment anchor, Adrianna Costa.
In April 2006, Handler began hosting The Chelsea Handler Show on E! In 2007, Handler performed with Comedy Central's Hour Stand-Up Comedy Tour across the United States.
Dottie Zicklin (of Dharma & Greg) and Julie Larson (of The Drew Carey Show) were creators and executive producers.
Handler served as executive producer, along with Tom Werner (of That '70s Show), Mike Clements (of The Life & Times of Tim), and Tom Brunelle (of Chelsea Lately).
In 2016, she filmed a documentary series for Netflix entitled Chelsea Does in 2016 comprising four episodes on marriage, Silicon Valley, racism, and drugs.
In February 2015, Handler said she envisioned a show more serious than Chelsea Lately.
Her stand-up comedy has also been televised on VH1's Love Lounge, Comedy Central's Premium Blend, and HBO's broadcast of the Aspen Comedy Festival.