By 1989, she was modeling and appearing in television commercials and would become a VJ for MTV in the early 1990s as "Duff." Since then she has had small roles in a handful of films including Dumb & Dumber, and by 1995 she was working as a correspondent for documentary film-maker Michael Moore on his television shows TV Nation and The Awful Truth. In 2006 Duffy hosted House of Tiny Terrors on TLC.
In 2008, Duffy began working with New York City's NYCTV through a series of emergency preparedness videos, based on the network's TV show, Secrets of New York. The videos, which mimic the unique style of the network's Emmy-award winning series are an attempt by City officials to raise awareness of the perils of natural disasters and preventative actions families should take to prepare for them.
Duffy was leading a relatively carefree youth in the heyday of her modeling career when in 1995 she was diagnosed with the relatively rare disease sarcoidosis. In her case, this affected her brain (neurosarcoidosis), leaving her partially paralyzed. She has so far battled it with a sense of humor, as is evident from her 2000 autobiography Model Patient: My Life as an Incurable Wise-Ass.
After the diagnosis she continued to model for Revlon and married John Lambros in 1997. They have since had a son named Jack "Lefty" Lambros.