The progress of clinical gene therapy trials during the last two decades has been remarkable, and its application has also expanded into various fields of human diseases. Among them, hereditary diseases such as the primary immunodeficiency diseases (PID) were considered suitable candidates for gene therapy because the therapeutic strategy was very simple, therefore, effective gene therapy may be obtained without significant difficulty compared to other more complex diseases such as cancer. Indeed, the first clinical gene therapy trial was safely performed and was in part, effective for adenosine deaminase (ADA) deficiency patients, a type of severe combined immunodeficiency diseases (SCID). However, because of certain unforeseen obstacles, it took approximately 10 years until the first curative effects were obtained for gene therapy in patients with X-linked SCID (X-SCID). Here, I review and discuss the background and historical events leading up to PID gene therapy, the safety issues, which unexpectedly arose after the successful report, and finally I will attempt to predict the future trends in this form of gene therapy.