MHC class I antigens are lost or downregulated in invasive tumors compared with autologous normal tissues. This is observed in most of the newly induced experimental tumors analyzed if they are cloned before passaging in vivo. Similarly, this is observed in 40%-90% of human tumors using the available panel of anti-HLA class I monoclonal antibodies. In both systems the tumor populations are heterogeneous for H-2/HLA expression and composed of clones that express different amounts of MHC class I antigens. This heterogeneity may have a profound influence on tumor behavior, considering the role that MHC antigens play in T and natural killer cell-mediated responses. It is possible that the tumor escape mechanisms from T and natural killer cells select variants that express a particular MHC class I altered phenotype. We review the MHC changes detected in different experimental as well as human tumors and demonstrate the relevance of these altered H-2/HLA tumor phenotypes for implementing immunotherapeutic strategies based on T or natural killer cell-mediated responses.