PURPOSE OF REVIEW: To discuss new data on the safety and efficacy of the ongoing gene therapy trials for primary immune deficiencies, the first reports of new trials and the preclinical developments that are likely to be translated to the clinic in the near future. RECENT FINDINGS: Both clinical successes and severe adverse events continue to be reported in trials of gammaretroviral gene therapy for severe combined immune deficiency-X1, adenosine deaminase-deficient forms of severe combined immune deficiency and chronic granulomatous disease. Insertion site analyses of recently reported trials on all of these diseases have discovered preferential insertion in the 5' ends of genes, including potentially dangerous ones such as proto-oncogenes and signal transduction and proliferation genes. Preclinical work on rodent and canine models has tested novel vectors, including lentiviruses and foamy viruses. SUMMARY: Gene therapy for the most common forms of severe combined immune deficiency can lead to immune reconstitution in most patients, although a minority of patients has derived minimal clinical benefit and some have suffered severe adverse events including death. Ongoing preclinical work attempts to address the latter shortcoming. Meanwhile, in the presence of a careful risk-benefit assessment, gene therapy remains an appropriate subject of clinical investigation.