The authors present a literature review exploring the possible association between APOE epsilon4 and cognitive dysfunction in multiple sclerosis. Differences in magnetic resonance (MR)-elicited brain pathology between epsilon4+ and epsilon4- multiple sclerosis patients were also considered. Overall, the cognitive literature suggests the likelihood of a gene-cognition relationship. A less certain picture pertains to the gene-MR data. Methodological considerations, however, leave many questions unanswered and the conclusions should be viewed in this light. No study has yet combined neuropsychological inquiry, brain imaging, and genetic determination, an approach that has the potential to pull together various pieces of the puzzle.