The ability of two highly metastatic tumor lines of DBA/2 (H-2d) origin to metastasize in various allogeneic normal or nude (nu/nu) mouse strains was investigated. Normal mice differing from DBA/2 at either the major histocompatibility complex or at minor histocompatibility loci were both able to reject rather high subcutaneous inocula of these tumor cells. F1 hybrids between susceptible and resistant strains could not reject the metastatic tumors. This suggests that tumor rejection was dependent on the recognition of allogeneic histocompatibility antigens. Two mouse strains appeared to be selectively resistant to the establishment of tumor metastases but could not prevent the progressive tumor growth at a local site. One was a new variant subline of DBA/2, provisionally designated as DBA/2/HD, the other was C57B1/6 (nu/nu), an athymic 'nude' mouse of C57B1/6 background. 'Nude' mice of BALB/c or C3H background were more or less susceptible to these tumors and their metastases. These studies demonstrate that the establishment of tumor metastasis is greatly influenced by genetic factors of the host. Resistance to local tumor growth seemed to require the presence of mature T lymphocytes while resistance to metastasis formation could be established in T-cell-deficient nude mice of certain genetic backgrounds.