The mechanistic studies on immune recognition of carbohydrates have been paved by the synergized advances in identifying the precise sugar structures recognized by the immune system, in analyzing the cellular and humoral components bearing the receptors for glycoconjugates, and production of the biological relevant carbohydrate epitopes by synthetic chemistry. In our current studies on natural antigenic glycolipids, we have found that the activation as well as the development of natural killer T cells (NKT) is guided by the information provided by glycolipid metabolism pathways in antigen presenting cells (APC). Based on genetic data and cellular immunological assays, we propose a neutral glycosphingolipid isoglobotrihexosylceramide, iGb3, as one of the candidates recognized by NKT cells under patho-physiological conditions such as cancer and auto-immune disease. New immunotherapy approaches might be explored by interfering with glycolipid metabolism or by directly supplementing rationally designed glycolipids.