Two recent studies will generate additional controversy in the therapeutic application of gene transfer to treat human diseases. Although these studies point to incremental and important advances, they highlight continued uncertainty about the relevance of studies in murine species with respect to human applications. In the first study, Manuel Grez and colleagues (Ott et al., Nat. Med., 2006) report the successful use of a gamma retrovirus vector to treat chronic granulomatous disease (CGD). CGD is caused by mutations in genes encoding proteins of the NADPH oxidase pathway. Neutrophils of CGD patients lack the ability to generate sufficient reactive oxygen radicals to kill certain types of bacteria and fungi. The disease is life-threatening and leads to a uniform reduction in life expectancy. Current treatments include aggressive use of antibiotics and anti-fungals, pharmacologic agents to enhance neutrophil killing and, in severe cases, stem cell transplantation. In the absence of appropriate stem cell donors, transplant procedures have high morbidity and mortality and are considered experimental. In this setting, Ott et al. utilized gene therapy in two adult patients with life-threatening infections resistant to standard therapies. The approach included subtle, but important, protocol modifications. First, informed by the success of the X-linked severe combined immunodeficiency (X-SCID) and adenosine deaminase deficiency SCID trials in Europe, this trial utilized low doses of busulfan for conditioning by myelo-reduction prior to infusion of gene-modified CD34+ cells. These cells were derived from granulocyte colony stimulating factor (G-CSF)“mobilized” peripheral blood, allowing relatively large numbers of CD34+ cells (~ 5 X 106/kg) to be infused. In addition, the investigators utilized a retrovirus vector in which the transgene, GP91phox, was expressed from the spleen focus-forming virus (SFFV) long terminal repeat (LTR). Expression of GP91phox in hematopoietic cells has been shown to be particularly high with this vector (Becker et al., Hum. Gene Ther., 1998, and Sadat et al., Gene Ther., 2003).