Although originally considered merely structural components of cellular membranes, glycosphingolipids (GSL) are now recognized as having critical effects on cellular physiology, including proliferation, differentiation, viral transformation and ontogenesis. In addition, a vast majority of human cancers have modified GSL composition compared to parental normal cells. These modifications may contribute to both tumor survival and exert striking effects on anti-tumor immunity. In this review, we discuss mechanisms of immune modulation by tumor-secreted GSL.