Transfer of genes into hematopoietic stem cells or primary lymphocytes has been a primary focus of the gene therapy field for more than a decade because of the wide variety of congenital and acquired diseases that potentially could be cured by successful gene transfer into these cell populations. However, despite success in murine models and in vitro, progress has been slow, and early clinical trials were disappointing due to inefficient gene transfer into long-term repopulating cells. The unique predictive value of nonhuman primate or other large animal models has become more apparent, and major advances in gene transfer efficiency have been made by utilizing these powerful but expensive and complex systems. This review summarizes more recent findings from nonhuman primate investigations focusing on hematopoietic stem cells or lymphocytes as target populations, and highlights specific preclinical issues, including safety. Results from studies using standard retroviral vectors, lentiviral vectors, adenoviral vectors, and adeno-associated viral vectors are discussed. Judicious application of these models should continue to be a priority, and advances should now be tested in proof-of-concept clinical trials.