The expression of L3T4 and Lyt-2 cell surface molecules separates T cells into two broad, non-overlapping subsets: typical T helper cells are L3T4+ Lyt-2-whereas most T killer cells and their precursors are L3T4-Lyt-2+. This review compares highly purified populations of unprimed L3T4+ and Lyt-2+ cells for their capacity to respond to class I vs. class II H-2 alloantigens. Various parameters are considered, including generation of mixed lymphocyte reactions (MLR) and cell mediated lympholysis (CML) in vitro, proliferative responses in irradiated mice, graft-versus-host reactions and skin allograft rejection. In all of these assays the two T cell subsets exhibit marked specificity in their response to H-2 alloantigens, L3T4+ cells responding only to class II and not class I differences and Lyt-2+ cells showing reciprocal specificity. Contrary to current dogma, the bulk of the evidence suggests that primary responses of Lyt-2+ cells do not depend on exogenous help provided by other T cells.