CD4 is critical for the development and function of the CD4+ subset of T cells and also subserves as the receptor for the human immunodeficiency viruses. Reports in the past year clarify the role and the molecular interactions of CD4 in these events. Determination of the structure of an extracellular fragment of CD4 reveals novel variations of the immunoglobulin fold and provides an atomic framework for interpretation of its interactions with MHC class II molecules and with gp120, the external envelope glycoprotein of the human immunodeficiency virus.