Somatic gene therapy involves the delivery and expression of a protective gene into a somatic organ. Cardiovascular gene therapy currently includes more than twenty clinical trials carried out worldwide. These trials evaluate gene delivery of vascular growth factors to the ischemic heart and legs in patients with coronary and peripheral artery disease, respectively. In contrast, no clinical trials have been carried out in gene therapy of heart transplantation. However, there is increasing experimental evidence for a therapeutic potential of this approach. Using a rat model of heart transplantation, we have shown that gene delivery of an inhibitor of interleukine-1, a pro-inflammatory molecule involved in allograft rejection, results in prolonged allograft survival. Another experimental study (5) has shown that gene transfer of a chimeric molecule comprising the cytotoxic T lymphocytic antigen-4 fused to an immunoglobulin (CTLA-4 Ig), which acts as a suppressor of T lymphocyte co-stimulation, induces an immune tolerance that is selective for the allograft. The recent development of gene transfer vectors that are capable of expressing a transgene for extended periods of time and in a regulatable manner represents an important step towards clinical applications in gene therapy of heart transplantation.