Animal models of MS, collectively referred to as experimental autoimmune encephalomyelitis (EAE), have shaped our concepts of neuroinflammation. Compared to EAE, studies with human MS-derived immune cells and tissues are facing a number of inherent obstacles. These include the tremendous genetic heterogeneity of the human population, as well as the fact that there is usually a long delay between the initiation of the autoimmune process and the emergence of clinical MS. MS-discordant monozygotic twins can help to overcome some of these hurdles. By controlling for genetic heterogeneity, the twin design is ideally suited for investigating external, non-genetic triggering mechanisms of neuroinflammation in human subjects. This may be illustrated by recent evidence supporting a pathogenetic role of the intestinal microbiota. Furthermore, some clinically unaffected co-twins show evidence of prodromal MS (“subclinical neuroinflammation“). This opens a window to investigate the earliest immunological changes linked to the initiation of the autoimmune process.