The introduction of recombinant genetic material into human cells for therapeutic purposes offers tremendous potential. However, almost from the beginning, the application of gene therapy has been characterized by the striking discrepancy between its promise and realization. Over the past 15 years, much has been learned about the various gene transfer systems and the requirements for efficient hematopoietic stem cell gene transfer. In the current review, we will summarize recent improvements in hematopoietic stem cell gene transfer, describe some of the promising results from recent clinical applications and the impediments that remain.