Four human CD1 isoforms (CD1a, -b,-c and -d) are now known to be antigen presenting molecules with the unique ability to present lipid antigens to T cells. CD1b and CD1d are found in acidic, late endocytic compartments, whereas CD1a and CD1c molecules accumulate at the plasma membrane and in early endosomes. Consistent with their differences in intracellular localization, most studies show antigen presentation by CD1b/CD1d to be dependent on endosomal acidification while CD1a/CD1c mediated antigen presentation is not. Taken together, recent advances in the analysis of CD1 molecules reinforce the hypothesis that the different CD1 isoforms are specialized to survey the lipid content of distinct intracellular compartments. This may help to explain the duplication and diversification of CD1 genes in humans and other mammalian species.