Many applications of somatic gene therapy relate to the immune system. Several forms of inherited immunodeficiencies are candidates for treatment by gene transfer. Adenosine deaminase (ADA) deficiency causes a form of severe combined immunodeficiency. Stable gene transfer and expression of human ADA has now been obtained in hematopoietic stem cells of mice and, more recently, in large animals. The human ADA has also been introduced and expressed in the primitive human hematopoietic progenitor cells that initiate long-term bone marrow culture. Clinical trials of gene therapy for ADA deficiency have been initiated. The initial protocols were aimed at the correction of peripheral blood T lymphocytes, but recent strategies are attempting ADA gene transfer into peripheral blood or bone marrow stem cells. Other immunodeficiencies that may soon be amenable to somatic gene therapy include leukocyte adhesion deficiency and chronic granulomatous disease. Gene therapy may also be applied to the treatment of acquired disorders. In theory, the hematopoietic stem cells of a human immunodeficiency virus (HIV)-infected patient could be genetically modified and used to reconstitute an HIV-resistant hematopoietic system. Various strategies are currently being investigated to achieve this "intracellular immunization" against HIV. These include the transfer of genes encoding recombinant soluble CD4 molecules, suicide genes under the control of HIV-inducible promoter, and anti-HIV ribozymes. Gene transfer could also be used in the treatment of cancer to increase the immune response of the host, to activate prodrugs specifically in tumors, or to protect normal tissues against the toxicities of conventional treatment. Recent progress in all of these applications of gene therapy is reviewed here.