Because of the anomalous acceptance of tumour homo- and even heterografts by Syrian hamsters, as opposed to the characteristic rejection of such grafts by various other mammalian species, a systematic investigation has been made of the ability of these animals to react immunologically against skin homografts. In each of four different closed colonies of Syrian hamsters (M.H.A., M.H., L.S.H. and C.B.) it has been found that skin homografts transplanted between most members of the same colony survived for at least 100 days. However, in the instances where destruction of intra-colony homografts took place, it was accompanied by an acute inflammatory reaction, just as in other rodents. With four of the six inter-colony combinations tested, most or all of the animals rejected their homografts in the classical manner after acute reactions, and the median survival times of these grafts (8.8 to 11.2 days) fell within the range characteristic of skin homografts transplanted between individuals of distant genetic relationship in other species. Moreover, 'second-set' homografts were destroyed with increased vigour, surviving for 6 days or less. Homograft survival in the other two colony combinations was asymmetric; whereas all M.H.A. hosts accepted homografts from L.S.H donors, the majority of M.H.A. homografts on L.S.H. recipients were rejected-many after chronic reactions. On the basis of these findings it is concluded that hamsters are potentially capable of rejecting homografts no less vigorously than other mammals. The specificity of graft acceptance or rejection has been investigated by grafting animals, after they had either fully accepted or destroyed previous skin homografts, with skin from other hamsters of the original or different colonies. The various results obtained gave further evidence of a multiplicity of transplantation isoantigens and of individual specificity in the Syrian hamster. Several of the L.S.H. animals which had rejected their original M.H.A. grafts fairly promptly, nevertheless, accepted grafts from at least one other M.H.A. donor for the duration of the experiment. Whereas all previously ungrafted M.H.A. hosts fully accepted L.S.H. grafts, yet following their exposure to incompatible C.B. grafts no less than 60% of M.H.A. animals rejected subsequent L.S.H. grafts. On the other hand, the life of C.B. skin homografts was significantly prolonged if they were transplanted to M.H.A. hosts already bearing L.S.H. homografts of some standing, instead of grafting them to normal, unoperated M.H.A. animals. Hence, isoantigens apparently shared in common by two different donor colonies lead in one situation to demonstrable immunity and in the other to prolonged graft survival. It is suggested on the basis of these findings that there are only a few 'strong' but at least several 'weak' histocompatibility antigens (genes) segregating in the Syrian hamster stocks so far tested. Subcutaneous administration of cortisone acetate (1 or 3 mg) every third day to C.B. animals more than doubled the expectation of survival of skin homografts from M.H.A. donors. However, such administration of cortisone was completely ineffective in prolonging the life of orthotopically transplanted skin heterografts from Chinese hamsters. Skin homografts exchanged between Chinese hamsters were destroyed in the usual manner with a median survival time of 8.8 (7.8 to 10.0) days.