Witherell received his PhD from the University of Wisconsin in 1973 and became an assistant professor at Princeton University in 1975. He moved to Santa Barbara in 1981 and in 1990 won the American Physical Society's Panofsky Prize for experiments on charm quarks at Fermilab. Witherell has also been chair of the Department of Energy's high-energy physics advisory panel and was elected to the National Academy of Sciences last year.

Witherell's current research programme concerns CP violation and the asymmetry between matter and antimatter. He has been closely involved in the design and construction of the BaBar detector which will study CP violation in B mesons at the recently completed B-factory at the Stanford Linear Accelerator Center.