Recent progress in understanding the genetic basis for human cancer has led to a variety of new perspectives regarding the pathogenesis of these diseases. A gene therapy clinical trial employing an expression vector/lipid complex encoding a major histocompatibility complex (MHC) class I protein, HLA-B7, was tested. This stimulated local anti-tumor responses which were useful in the generation of effector cells. We have further explored the cellular and molecular basis of immune suppression in malignancy. One mechanism associated with inhibition of immune function and induction of lymphoid apoptosis involves the CD95-CD95 ligand (CD95L) system. In vivo gene transfer of CD95L inhibited the growth of CD95+ tumor cell lines, as expected. Unexpectedly, marked regression was observed after CD95L gene transfer into a colon carcinoma line which does not express CD95, caused by a potent inflammatory reaction that was induced. Our findings suggest that gene transfer of CD95L generates apoptotic and proinflammatory responses which can induce regression of both CD95+ and CD95− tumors. More recently, we have begun to define the molecular basis for the suppression of inflammation by tumors and in immune-privileged sites. Our data indicate that TGF-β suppresses the proinflammatory effects of CD95L. Because both CD95L and TGF-β1 inhibit T cell function, we suggest that these cytokines contribute to the development of immunologic tolerance. This information may be useful in regulating responses to tumors. In summary, advances in the understanding of molecular immunology and gene delivery have provided new insights into molecular genetic strategies that may be applied to the treatment of cancer.