T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is a type I transmembrane receptor that is constitutively expressed at high levels on NK cells, and also expressed on specific subsets of CD4+ and CD8+ T cells, on subpopulations of macrophages and DCs, and on monocytes, albeit to a lesser extent than on NK cells. TIM-3 was originally identified as a marker of terminally differentiated CD4+ Th1 cells, and subsequently associated with T cell exhaustion and impaired virus-specific T cell responses in HIV-1, hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. To date, three ligands have been described for TIM-3, including Galectin-9 (Gal-9), cell surface phosphatidylserine, and the high-mobility group box 1 (HMGB1) protein. Gal-9 is highly expressed in immune tissues, and engagement of TIM-3 by Gal-9 triggers apoptosis in CD4+ Th1 cells, T cells and thymocytes. TIM-3 signaling on immune cells can trigger either inhibitory or activating signals.