Gene therapy is a promising endeavor for the treatment of disease in the 21st century. The key to capitalize on this venture lies in the availability of efficient gene transfer and expression tools. Viral vectors are useful vehicles for the delivery of foreign genes into target cells, and retroviral vectors have been popular because of their ability to integrate into the host cell genome and maintain persistent gene expression. Recent studies of the human immunodeficiency virus (HIV) have demonstrated that lentiviruses, members of the retroviral family, have the ability to infect cells at both mitotic and post-mitotic stages of the cell cycle. This article aims to analyze the molecular genetics, review existing systems and applications, and address problems as well as potential future developments of the lentiviral vector systems.