This article discusses advances in HIV gene therapy, focusing on ex vivo approaches. Early gene therapy studies showed promise for curing heritable diseases, but genotoxic events led to a pause in clinical trials. Recent genetic engineering advances have renewed interest, resulting in the approval of the first gene therapy product targeting genetic mutations in 2017. Ex vivo gene therapy, which involves modifying cells outside the body before reinfusion, offers advantages such as cell characterization, selection of desired properties, and reduced immune rejection through the use of autologous cells. The review highlights the stages of ex vivo gene therapy, current research developments, and summarizes HIV gene therapy studies, most of which use the ex vivo approach. HIV cure efforts face challenges due to the latent viral reservoir, which is resistant to current therapies. Strategies to cure HIV include stem cell transplantation, "Shock and Kill" to activate and eliminate the virus, gene editing to remove or inactivate the virus, and the "Block and Lock" approach to maintain the virus in a latent state. The majority of HIV gene therapy studies use the ex vivo method, and the article provides an overview of the current clinical trials and research in this area. Ex vivo gene therapy involves sourcing hematopoietic stem cells (HSCs) from the patient or a donor, modifying them, and reinfusing them. The article details the sources of HSCs, including bone marrow, peripheral blood, umbilical cord, and placenta. It also discusses the isolation, purification, and enrichment of HSCs, as well as the modification of these cells with genes of interest. The article highlights the use of viral vectors, particularly lentiviral vectors, for gene delivery, and addresses challenges such as transgene silencing, insertional mutagenesis, and the need for safe and effective delivery methods. The article also covers strategies to enhance the engraftment of gene-modified HSCs, including conditioning regimens to clear the hematopoietic stem cell niche and in vivo selection techniques to preferentially select transduced cells. Recent developments in niche clearance, such as the use of monoclonal antibodies conjugated to drugs, are also discussed. Overall, the article provides a comprehensive overview of the current state of HIV gene therapy, emphasizing the importance of ex vivo approaches in advancing this field.This article discusses advances in HIV gene therapy, focusing on ex vivo approaches. Early gene therapy studies showed promise for curing heritable diseases, but genotoxic events led to a pause in clinical trials. Recent genetic engineering advances have renewed interest, resulting in the approval of the first gene therapy product targeting genetic mutations in 2017. Ex vivo gene therapy, which involves modifying cells outside the body before reinfusion, offers advantages such as cell characterization, selection of desired properties, and reduced immune rejection through the use of autologous cells. The review highlights the stages of ex vivo gene therapy, current research developments, and summarizes HIV gene therapy studies, most of which use the ex vivo approach. HIV cure efforts face challenges due to the latent viral reservoir, which is resistant to current therapies. Strategies to cure HIV include stem cell transplantation, "Shock and Kill" to activate and eliminate the virus, gene editing to remove or inactivate the virus, and the "Block and Lock" approach to maintain the virus in a latent state. The majority of HIV gene therapy studies use the ex vivo method, and the article provides an overview of the current clinical trials and research in this area. Ex vivo gene therapy involves sourcing hematopoietic stem cells (HSCs) from the patient or a donor, modifying them, and reinfusing them. The article details the sources of HSCs, including bone marrow, peripheral blood, umbilical cord, and placenta. It also discusses the isolation, purification, and enrichment of HSCs, as well as the modification of these cells with genes of interest. The article highlights the use of viral vectors, particularly lentiviral vectors, for gene delivery, and addresses challenges such as transgene silencing, insertional mutagenesis, and the need for safe and effective delivery methods. The article also covers strategies to enhance the engraftment of gene-modified HSCs, including conditioning regimens to clear the hematopoietic stem cell niche and in vivo selection techniques to preferentially select transduced cells. Recent developments in niche clearance, such as the use of monoclonal antibodies conjugated to drugs, are also discussed. Overall, the article provides a comprehensive overview of the current state of HIV gene therapy, emphasizing the importance of ex vivo approaches in advancing this field.