The CD1 proteins are a family of non-polymorphic and MHC class I-related molecules that present lipid antigens to subsets of T lymphocytes with innate- or adaptive-like immune functions. Recent studies have provided new insight into the identity of immunogenic CD1 antigens and the mechanisms that control the generation and loading of these antigens onto CD1 molecules. Furthermore, substantial progress has been made in identifying CD1-restricted T cells and decoding the diverse immunological functions of distinct CD1-restricted T cell subsets. These findings shed new light on the contributions of the CD1 antigen-presentation pathway to normal health and to a diverse array of pathologies, and provide a new impetus for exploiting this fascinating recognition system for the development of vaccines and immunotherapies.