Hematopoietic stem cell transplantation (HSCT) has proven successful for the treatment of a host of genetic and malignant diseases of the blood, but immune barriers to allogeneic tissue transplantation have hindered wider application. Likewise, gene therapy now appears effective in the treatment of various forms of immune deficiency, and yet insertional mutagenesis from viral gene transfer has raised safety concerns. One strategy for addressing the limitations of both gene therapy and allogeneic transplantation entails the creation of pluripotent stem cells from a patient's own somatic cells, thereby enabling precise in situ gene repair via homologous recombination in cultured cells, followed by autologous tissue transplantation. In murine model systems, the methods of somatic cell nuclear transfer, parthenogenesis, and direct somatic cell reprogramming with defined genetic factors have been used to generate pluripotent stem cells, and initial efforts at therapeutic gene repair and tissue transplantation suggest that the technology is feasible. Generating patient-specific autologous pluripotent stem cells provides an opportunity to combine gene therapy with autologous cell therapy to treat a host of human conditions. However, a number of technical hurdles must be overcome before therapies based on pluripotent human stem cells will appear in the clinic.