Molecules of the major histocompatibility complex (MHC) bind protein-derived peptide antigens and present them to T cells. This has been a central dogma in modern immunology, and our appreciation of a variety of cell-mediated immune responses has been based only on this paradigm. However, we now know that T cell recognition also involves non-peptide antigens. Studies over the past several years have established a new paradigm that non-MHC-encoded molecules of the CD1 family mediate presentation of lipid antigens to T cells, and unraveled their significant role in microbial immunity, tumor immunology, and autoimmunity. Identification of a novel pathway for T cell activation mediated by CD1 molecules opens a possibility for new therapeutic strategies, including development of lipid-based vaccines.