T cell immunoglobulin and mucin domain (TIM)-3 is a molecule expressed on terminally differentiated murine Th1 cells but not on Th2 cells. Identification of galectin-9 as a ligand for TIM-3 has now firmly established the TIM-3-galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. TIM-3 is similarly expressed on human Th1 cells and not on Th2 cells, which suggests that TIM-3 might also contribute to Th1 regulation in humans. In addition, genetic data associate the TIM locus and specific TIM-3 polymorphisms with various immune-mediated diseases. Most importantly, recent data suggest a novel paradigm in which dysregulation of the TIM-3-galectin-9 pathway could underlie chronic autoimmune disease states, such as multiple sclerosis.