Publisher Summary Since the mid‐1990s, various approaches have been described having the capacity to suppress human immunodeficiency virus‐1 (HIV‐1) infection or replication in cultured cells. The work performed in cell culture systems has indicated overall that the goal of rendering cells resistant to HIV‐1 infection by gene transfer is attainable. A major challenge, however, has been the adaptation of these genetic strategies to a clinical setting. This chapter focuses on the attempts that have been made to render T cells resistant to HIV‐1 infection and on the experience gained from the results of clinical trials. The chapter discusses the limits of the experimental approaches implemented, to describe the present status of research, and highlights the advancements that are required before gene therapy of HIV‐1 infection that might eventually become clinically successful. Clinical success appears highly desirable, especially in light of the limitations of present antiretroviral therapy in terms of long‐term toxicity, emergence of drug‐resistance HIV variants, and inability to eradicate infection.