The type II bare lymphocyte syndrome (BLS) or major histocompatibility complex class II (MHCII) deficiency is a severe combined immunodeficiency (SCID) that is characterized by the absence of constitutive and inducible expression of MHCII determinants on immune cells. Four complementation groups of BLS have been defined, and they result from mutations in DNA-bound activators and the coactivator for MHCII transcription. Recently, all complementation groups of BLS patients have been accounted for. Studies of the syndrome and specific mutations reveal important lessons for the genetics of the immune response.