Thirty eight years after the discovery of human immunodeficiency virus (HIV) more than 30 antiretrovirals have been introduced. HIV at present can be managed though, it comes with consequences such as toxicity because of long term use of antiretroviral, development of resistance by HIV-1 strains and other viral or bacterial infections associated with it, also a major challenge such as latent HIV in reservoirs, other like socio-economic problem in the developing world has been of considerable concern. The benefits of highly active antiretroviral therapy (HAART) in the developed countries far outweighed those in the underdeveloped nations. HIV belongs to the genus Lentivirus and family Retroviridae, possess a diploid RNA and a cone shaped capsid core particles. The virus consists of major and minor structural and nonstructural proteins that perform different roles in the virus life cycle. In this review we seek to give a comprehensive account of the past, present and future direction in the development of antiretroviral drug. There are five classes of antiretroviral inhibitors which target HIV-1’s reverse transcriptase, protease, integrase, envelope fusion and co-receptor binding thereby disrupting virus replicative cycle. Strategies have emerged on how to better manage HIV patients such as simplification of drugs, complete HAART withdrawal, use of microbicides, targeted PrEP (pre-exposure prophylaxis), post-exposure prophylaxis (PEP), targeted drug therapy and vaccine development. There are several host (example; CRIM-1) proteins and virus (example; Rev, Tat and capsid) proteins that are currently been explore and could serve as potential drug targets, also the introduction of monthly injection, stem cells transplantation, having a deeper understanding of the biology of HIV epigenetic regulation, targeting HIV reservoirs through functional and sterilizing cure, thus the need for intense research in these directions.