Dr. Mahaffey's professional career is in exposure assessment and toxicology of metals. She has worked extensively in the area of food safety. Following graduate training in nutritional biochemistry and physiology at Rutgers University, she completed post-doctoral training in neuro-endocrinology at the University of North Carolina School of Medicine. Her research has been on susceptibility to lead toxicity with greatest focus on age and nutritional factors resulting in more than 100 publications in this area. During her long career with the United States Government she has been influential in lowering lead exposures for the United States population through actions to removal lead from foods and beverages, and from gasoline additives during the 1970s and 1980s.

In the past decade, Dr. Mahaffey has been actively involved in risk assessments for mercury. She was the author of the NIH Report to Congress on Mercury, and a primary author of US EPA's Mercury Study Report to Congress. These reports emphasized risk of developmental deficits caused by methylmercury exposure during development of the nervous system. Dr. Mahaffey was one of the primary developers of US EPA's Mercury Research Strategy which was released in late 2000. Along with other team members, she was responsible for the 2001 EPA/FDA national advisory on fish consumption. Dr. Mahaffey was one of a group of three EPA health scientists who revised the basis for EPA's Reference Dose for Methylmercury which was used in developing the Methylmercury Water Quality Human Health Criterion. In 2002 she received EPA's Science Achievement Award in Health Sciences for this work. This is EPA's highest health sciences award and is presented in conjunction with the Society of Toxicology.

Currently Dr. Mahaffey is the Director of the Division of Exposure Assessment, Coordination and Policy within the Office of Science Coordination and Policy of OPPTS, US EPA. This division runs US EPA's Endocrine Disruptor Screening and Validation Program. Dr. Mahaffey remains active in research and developing US EPA's policies on methylmercury.