Despite the success of antiretroviral therapy in suppressing HIV-1 replication and extending the life of HIV-1 infected individuals, this regimen is associated with risks for non-AIDS morbidity and mortality, requires life commitment, and has a high cost. In this context, gene therapy approaches that have the potential to cure HIV-1 infection present a clear option for eradication of the virus in the next decades. Gene therapy must overcome concerns related to its applicability to HIV-1 infection, the safety of cytotoxic conditioning required for cell-based approaches, clinical trial design, selection of gene-modified cells, and the restrictive cost of manufacturing and technology. These concerns are discussed herein in the context of the most relevant gene therapy studies conducted so far in HIV/AIDS.