Gangliosides are neuraminic acid-containing glycosphingolipids that are anchored into the cell membrane lipid bilayer by lipophilic ceramide chains. They are overexpressed on tissues of neuroectodermal origin, and particularly in tumors such as melanomas, sarcomas, neuroblastomas, astrocytomas, and small cell lung cancers. Both active and passive immunotherapy trials have identified gangliosides as uniquely effective targets for antibody mediated melanoma immunotherapy. Induction of antibodies against GM2 by vaccination has correlated with an improved prognosis in American Joint Committee on Cancer (AJCC) stage III melanoma patients and vaccines containing GM2 chemically conjugated to keyhole limpet hemocyanin (KLH; GM2-KLH) plus the immunologic adjuvant QS-21 have proven to be consistently immunogenic. Phase III trials with this vaccine are ongoing in patients with melanoma in the United States, Canada, Europe, Australia, and New Zealand. GD2, fucosylated GMI, and GD3-KLH conjugates plus QS-21 are also consistently immunogenic, inducing IgM and IgG antibodies in the majority of patients. Polyvalent ganglioside-KLH conjugate plus QS-21 vaccines should be available in early 1999 for testing in phase II and III clinical trials.