The role of self-antigen recognition in the development of T and B cells of the adaptive immune system has been studied in several different ways. We have shown that CD4 T cells are selected on self-peptide:self-MHC class II ligands, and in the periphery, they are sustained by contact with the same or similar ligands. We have also observed that B cells are positively selected on unknown and presumed self-ligands. We have used this information to explore autoimmune diseases as well. Finally, we have recently identified the innate immune system as playing a crucial role in regulating expression of costimulatory molecules that are required for induction of adaptive immune responses.