CD1 proteins mediate T cell activation in response to self and foreign lipids, including lipid antigens from the intracellular pathogen Mycobacterium tuberculosis. During natural infections, myeloid cells migrate to sites of infection and use microbial pattern recognition receptors to internalize live bacteria and lipid antigens into the endosomal network. New studies show that certain CD1 proteins are particularly receptive to binding lipid antigens in the low pH environment of endosomes. Therefore, the endosomal network may represent a depot for concentrating and then selectively presenting exogenous foreign lipid antigens to T cells.