Recent studies of T cell responses to microbial antigens have uncovered a previously unknown pathway for antigen presentation involving a family of proteins known collectively as CD1. As with MHC class I and II antigen presenting molecules, the membrane distal domains of CD1 proteins form a hollow groove, which captures structurally diverse antigens to form antigen complexes. However, the ligands of CD1 proteins are not traditional peptide antigens, but instead are amphipathic lipids from mammalian cells and microbial pathogens, including diacylglycerols, sphingolipids, polyisoprenoid lipids and mycolyl glycolipids. This points to a new function of T cells in responding to changes in cellular lipid content that occur during infection and other forms of stress. Our studies have identified a family of the foreign glycolipids presented by CD1b to be glucose monomycolates (Science 278, 283-8). In addition, we identified the first known class of antigens presented by human CD1c proteins to be mannosyl-b-1 isoprenoid glycolipids (Nature, 404, p.884). Definition of the antigenic epitopes on these glycolipids clarifies the general molecular mechanism by which CD1 proteins present antigens to T cells. Current studies are aimed at defining the molecular pathways by which mycobacteria produce antigenic lipids (J Exp Med 192, p.965), the pathways by which glycolipids are taken up by cells (Nature Immunol, 3, p.435) and discovery of new antigenic compounds. These studies may lead to the development of immunomodulatory lipids as therapies for patients with autoimmune, infectious and neoplastic diseases.