Human immunodeficiency virus (HIV) targets the host immune system causing acquired immunodeficiency syndrome (AIDS). Although significant advancements have been made on investigating HIV and related infections, eradicating the virus from the host immune system is still challenging. Nevertheless, the combination therapies using drugs targeting different stages in the viral life cycle are used for treatment in which HIV protease plays a vital role. Hence, it is essential to understand the structure and function of HIV protease. This review focuses on these aspects from different perspectives such as catalytic mechanism, subtypes and role of flaps in drug binding. Further, we highlight the factors affecting drug binding, evolution of drug resistance, and inhibitors reported in the literature using 3D QSAR studies.