Human immunodeficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS), continues to represent a major global health and socio-economic concern, particularly in low- and middle-income regions. With an estimated 38 million individuals currently living with HIV, the epidemic has resulted in profound and widespread consequences. This chapter investigates how precision medicine can enhance HIV treatment strategies, with a particular emphasis on African populations. It begins with a concise overview of HIV’s origin and transmission and then moves on to examine the distribution and burden of the disease across Africa. Key factors discussed include pharmacogenetics, socio-environmental dynamics, and microbiome influences, all of which are critical to tailoring HIV care within the African context.