In contrast to the excellent surveillance against tumors induced by the ubiquitous viruses in their natural host species, spontaneous tumors developing naturally, without experimental interference, evoke little or no rejection reaction. This may be viewed in relation to the natural history of tumors. In most cases, tumors evolve in several steps, with a successful of clonal variants following each other, characterized by increasing independence of host regulations (including immune restrictions). This process is commonly designated as tumor progression. In all probability, selection for nonrejectability is part of this process. Selection of the host for rejecting capacity is unlikely to play any major role, since the overwhelming majority of the naturally occurring tumors arise after the host has passed the peak of its reproductive period. The nonrejectability of spontaneous tumors may be overcome by target-cell modification, eg, by chemical coupling, somatic cell hybridization, or viral xenogenization. Furthermore, genetic analysis of the F1 resistance effect in relation to seemingly nonrejectable tumors may reveal the existence of specific immune-response (Ir) genes that can influence the recognition of tumor-associated membrane changes by the host immune system.