Dr. Mathis obtained a PhD from the University of Rochester, and performed postdoctoral studies at the Laboratoire de Génétique Moléculaire des Eucaryotes in Strasbourg, France and at Stanford University Medical Center. She returned to Strasbourg at the end of 1983, establishing a laboratory at the LGME [later the Institut de Genetique et de Biologie Moleculare et Cellulaire (IGBMC)] in conjunction with Dr. Christophe Benoist. The lab moved to the Joslin Diabetes Center, Boston in 1999. Through 2008, Dr. Mathis was a Professor of Medicine at Brigham and Women's Hospital and Harvard Medical School, and Associate Research Director and Head of the Section on Immunology and Immunogenetics at Joslin. Dr. Mathis is currently a Professor in the Department of Immunology at HMS, and holder of the Morton Grove-Rasmussen Chair in Immunohematology. She is also an Associate Faculty Member of the Broad Institute. She presently serves on Advisory Boards of the HHMI, Genentech, Pfizer and Amgen (amongst others) and of several research institutes worldwide. Dr. Mathis was elected to the US National Academy of Sciences in 2003, the German Academy in 2007, and the American Academy of Arts and Sciences in 2012. She received the FASEB Excellence in Science Award in 2016.

Her lab works in the fields of T cell differentiation, autoimmunity and inflammation. She has trained over 150 students and postdoctoral fellows.