Gene-marking studies were the first gene-transfer protocols approved for human use. Their intent was not directly therapeutic but rather to track the behavior and fate of cells in vivo, and to use this information to improve treatment protocols. For more than fifteen years, gene-marking studies using retroviral vectors have provided invaluable information about the biology of human hematopoietic cells and T lymphocytes, and have helped guide cell therapies intended to treat malignant disease. Although the safety record of marking studies has been impeccable, the development of leukemia by immunodeficient children treated with retroviral vectors cast a pall over the entire field and essentially brought the era of pure gene-marking studies to an abrupt end. Paradoxically, the impetus these events gave to studying retroviral integration sites in host cell DNA emphasized the additional information that marker studies could provide about the behavior of cells at the clonal level. As confidence has slowly returned, marker studies have reappeared, usually as components of gene therapy protocols in which a marker gene or sequence is incorporated to allow the modified cells to be tracked or imaged in vivo. Hence, gene marking continues to have much to offer in terms of our understanding of the behavior, fate, and safety of gene-modified cells in vivo.