There is considerable evidence that T-cell activation to soluble antigens occurs only if this is processed by macrophages and displayed appropiately on the cell membrane in association with products of the genes of the MHC. The genes responsible differ according to the cells and antigens involved. For cytotoxicity, targets and killer T cells must share K- or D-region gene products. For delayed-type hypersensitivity to FGG in mice, I-A identity is necessary; for DNFB, identity at either the I, K, or D region is sufficient. Experiments using three different approaches do not support the notion that these genetic constraints are due to the necessity for the T cell and stimulator cell to match an identical gene product or cell-interaction molecule. Rather, they favor the hypothesis that there are receptors on the activated T cell which recognize antigen and products of genes of the MHC. The implications of the results are discussed in terms of (1) different T-cell subsets, (2) the mode of action of Ir genes, and (3) the possible parallel evolution of T-cell receptors for antigen and gene products of the MHC.