Retroviruses engineered to produce human proteins and then transduced into a wide variety of types of cells are part of a strategy for gene therapy. In epidermal keratinocytes, expression of a transgene introduced by a retroviral transduction is expressed in culture for long periods of time, but is not sustained in vivo. Fenjves et al (p. 576) used the blood clotting protein, factor IX, examine this issue. Human keratinocytes in culture were transduced with retroviruses containing cDNA for factor IX. The transduced cells, which expressed factor IX in culture, were grafted onto nude mice, and factor IX was measured in their serum. “Shut off” of the foreign protein was noted in vivo even though these same cells continued to secrete factor IX in culture. The authors showed that a “control” protein produced constitutively by the human keratinocytes, apolipoprotein E, was still present in the serum of the grafted mice beyond the time when factor IX was no longer detectable. Since the human cells were not lost, and since there was no block to secretion of protein by grafted cells, the authors suggest that the lack of sustained expression of the transgene is due to inactivation of the retroviral promoter in vivo. Understanding of the mechanism of this loss of expression is crucial for the future of gene therapy. The authors suggest, and the work of others suggests, that use of tissue-specific promoters, such as a promoter controlling production of a human epidermal protein, may help overcome this problem.