Data in mice suggest that in vivo selection strategies will expand the numbers of transduced hematopoietic stem cells (HSC) to levels sufficient for clinical therapies, and it is argued that comparable strategies will benefit larger animals and humans. To test this assumption, we performed virtual gene therapy in mouse and cat, species in which the in vivo kinetics of HSC are defined. In the simulated experiments, 10% of HSC and 50% of short-term repopulating cells were transduced with a gene allowing a conditional replication or apoptosis advantage. After transplantation, differentiation proceeded stochastically and contributions of transduced cells were tracked for 2 years. Fifty independent transplantations were simulated per species for each analysis. When transduced HSC had a 2-fold increased chance of replication (self-renewal) extending for 4, 10, or 20 weeks after transplantation, or a 5-fold replication advantage extending for 4 weeks, results in mice were far better than in cat, a larger animal, with slower baseline HSC cell cycle kinetics. Similarly, when transduced HSC had a 2-, 4-, or 10-fold decreased chance of apoptosis, extending for 20 or more weeks after transplantation, the murine studies were poor predictors of feline results. Simulation may allow one to optimize and/or understand the limitations of a gene therapy strategy.