Functional differentiation between the four antigen-presenting human CD1 isoforms, CD1a-d, is achieved through their lipid-binding properties. Compared to structurally-related MHC class I molecules, a far greater proportion of the CD1/ligand complex volume is made up by the ligand or ligands buried within the antigen binding groove. This is most pronounced in CD1b and CD1c. In consequence, the degree of ligand saturation of the antigen binding grooves in these CD1 proteins can exert major impact on overall CD1 conformation and thus T cell recognition. In my talk, I will discuss our group’s recent insights into CD1b and CD1c ligand structures, their binding to human T cell receptors, and implications for human disease.