The tremendous potential of stem cell-directed gene therapy has recently been demonstrated with the cure of children suffering from X-linked severe combined immunodeficiency (X-SCID) and adenosine deaminase deficiency [1–3]. A new era of medicine appeared to be on the horizon, but enthusiasm was quickly dampened after it became evident that this clinical success had not come without severe adverse events (SAEs). Unfortunately, 2 of 10 children treated with gene therapy developed leukemia [4, 5]. Thus, the very study that was initially regarded as the breakthrough for stem cell gene therapy is now considered by some as the breakdown for the field. To reach the point where both the great promise and the potential risk are equally apparent has taken over 20 years of developing and refining gene transfer techniques. A major obstacle has been the lack of tissue culture or rodent models predictive for stem cell gene transfer in humans. In this review we discuss the important contributions of large animal studies to the enormous progress in hematopoietic stem cell gene transfer and how large animal models can help to further improve efficiency and safety of stem cell gene therapy.