The CD1 family of glycosylated cell surface receptors binds and presents lipid antigens for T cell recognition and activation. Crystal structures of CD1-lipid complexes reveal differences in the mode of presentation of lipids by CD1 group 1 (CDla, CDlb, and CDlc) and group 2 isoforms (CDld). For group 1, especially CDla and CD1b, the lipid backbone is anchored inside the hydrophobic binding grooves (lipid anchoring), whereas, for group 2 CDld, a precise hydrogen-bonding network positions the polar ligand headgroups in well-defined orientation at the T cell recognition surface (headgroup positioning). In addition, small, but important, structural changes occur on the surface of CDld upon binding of the potent invariant NKT cell agonist alpha-galactosylceramide due to increased polar interaction with the alphal and alpha2 helices. No such ligand-induced, conformational changes have yet been reported for any group 1 CD1 complexes, even upon binding of chemically diverse antigens, such as dual alkyl chain sphingolipids vs single alkyl chain lipopeptides. These structural data have already been successfully translated into the design of enhanced lipid activators of NKT cells and will likely continue for design of other chemotherapeutic agents or immunostimulatory compounds for a variety of immune-mediated diseases.