Stefansson's academic work was focused on neurodegenerative disease. The protein biology approach to this research involved trying to map complex processes using limited samples, mainly of brain tissue from deceased patients. Although publishing steadily, Stefansson was frustrated by the pace of progress and often by not knowing whether the proteins he was characterizing were involved in causing disease or the product of the disease process. He and his colleagues came to question even the accepted definition of multiple sclerosis (MS) as an autoimmune disease.