Gene-marking studies were the first approved clinical protocols introducing exogenous genetic material into human cells. Such studies were never intended to provide direct therapeutic benefit. Instead, they were expected to provide information about normal cell biology and disease pathogenesis that could not be obtained in any other way. However, the information gained from such studies has had a significant impact on disease management. Gene-marking studies have provided valuable insights into the biology of the human stem cell, factors that influence the efficiency of gene transfer, mechanisms of relapse after stem cell transplantation, and the pharmacodynamics of adoptive cellular immunotherapy. With continuing advances in gene-marking technology, the value of the information provided by these studies increases, thereby ensuring their continued relevance to the field of gene transfer.