Differentiation antigens can be simply defined as cell surface antigens that distinguish one cell type from another. The Ly-6 family of cell surface antigens might easily be regarded as a prototype for the analysis of the function of differentiation antigens on immunocompetent cells. Although a number of studies with antisera, in the late 1970s, established that the Ly-6 antigens exhibit an unusual pattern of expression on T and B lymphocytes, functional studies failed to demonstrate that the expression of Ly-6 defines a unique subpopulation of immunocompetent cells. Paradoxically, the development of anti-Ly-6 monoclonal antibodies led to a further decline in interest in this group of antigens, as the complexity of the results relegated Ly-6 to the realm of the die-hard immunogeneticist. Over the past five years, interest in Ly-6 has been rekindled and in this review Ethan Shevach and Patricia Korty summarize recent studies on the serology, biochemical and molecular structure, and the function of the products of this multigene family.