The advent of safe and practical means to correct, enhance or protect blood cells at the genetic level offers tantalizing therapeutic perspectives. At present, gene delivery using a replication-defective retrovirus is the most efficient method to stably transduce hematopoietic cells. The successful adaptation of retroviral infection to hematopoietic stem cells requires optimized transduction conditions that maximize gene transfer while preserving the cells' potential for engraftment and longterm hematopoiesis. The successful establishment of effective transduction protocols hinges on retrovirus biology as well as stem cell and transplantation biology. Interestingly, the genetic approach could permit novel strategies to promote host repopulation by transplanted stem cells. However, regulated and predictable expression of any transgene integrated at random chromosomal locations cannot be taken for granted. Investigation of the control of transgene expression and prevention of vector silencing will become increasingly important.