For centuries the thymus remained an enigmatic organ with unknown functions. The first demonstration of its crucial role in establishing the development of a normal immune system was provided in 1961, when it was shown that mice thymectomized immediately after birth had poorly developed lymphoid tissues, impaired immune responses and inordinate susceptibility to intercurrent infections. Although thymus lymphocytes were believed to be immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating and giving rise to a progeny of cells that could not produce antibody, but enabled other lymphocytes, derived from bone marrow, to differentiate to antibody-forming cells. This was the first unequivocal demonstration, in mammalian species, of the existence of two major interacting subsets of lymphocytes, T and B cells. It required a re-evaluation of many immunological phenomena, such as tolerance, memory and autoimmunity, and it was followed by an avalanche of work elucidating many of the mysteries of the immune system.