Despite major advances in understanding the mechanisms of tumor immunity, its successful translation into effective tumor immunotherapy is hindered by the ability of tumors to foster a tolerant microenvironment and to activate a plethora of immunosuppressive mechanisms. Among different strategies employed by tumors to thwart immune responses, shedding of immunosuppressive molecules, such as sialic acid-containing glycosphingolipids, gangliosides, by the tumor is one important strategy. Aberrant and elevated expression of gangliosides has been demonstrated on the surface of cancer cells. Here we discuss about the molecular mechanisms underneath the contribution of tumor gangliosides in targeting multiple steps of T cell response. We shall also underscore the contribution of T-regulatory, NK and dendritic cells in this immunosuppressive network. Inhibitory effects of gangliosides ultimately converge to T cell apoptosis in receptor-dependent and -independent manners via IL-2 deprivation, ROS production, cytochrome c release, NFkappaB inhibition and caspase activation. Current wealth of information promises a future scenario in which synchronized blockade of immunosuppressive mechanisms and removal of inhibitory signals might be effective in overcoming immunological tolerance and promoting tumor regression.