This chapter discusses human anti-pig T-cell responses as this system is particularly relevant to clinical transplantation. T-cell recognition of foreign major histocompatibility complex (MHC) antigens has represented a challenging enigma for cellular immunologists over more than three decades. First, T-cell reactivity to nominal antigens can be detected only if the individual had been primed in vivo with the respective antigen, or after in vitro immunization by multiple antigenic stimulations. The second major difference between T-cell responses to allogeneic or xenogeneic cells and reactivity to nominal antigens resides in the lack of self-MHC restriction and processing requirements for recognition of foreign cell surface MHC antigens. Elucidation of the three-dimensional structure of class 1(11) and class II MHC (17) molecules, together with major advances in our understanding of antigen processing and presentation, had clarified considerably the molecular basis of direct T-cell recognition. The emerging picture is that both the allogeneic MHC molecule itself and the bound peptides may each independently contribute to reactivity and, furthermore, that peptide binding to MHC may induce conformational changes in the MHC molecule itself that affect recognition. Indirect recognition of xenogeneic antigens is likely to induce more powerful immune responses than human allogeneic MHC antigens, because of the larger number of foreign antigenic peptides that result from the processing of xenogeneic proteins. In conclusion, xenografts, like allografts, elicit T-cell-mediated immune responses against foreign antigens present in the graft, via the direct and indirect recognition pathways.