The antigenic repertoire of T cells has long been considered as exclusively composed of proteins and peptides. This view has been recently challenged by the discovery of CD1 molecules, a set of weakly polymorphic MHC class I-related receptors able to present lipid antigens to T cells. An updated picture of the biology of human CD1-restricted T cells is provided here, which highlights the unique features of these lymphoid effectors and the way they synergize with other innate and adaptive immune players to ensure protective immunity against tumors and pathogens.