Since AIDS was first recognized in the early eighties, more than 25 million people have died and tens of millions of people have been infected with HIV. Presently more than 40 million men, women and children are living with HIV. In the most affected countries, AIDS dramatically diminishes life expectancy and economic potential, by killing people in the prime of their lives, and undermines the future generations by creating millions of orphans. Although HIV infection rates are especially dramatic in Africa and South-eastern Asia, in the most populous countries including China, Indonesia and Russia, the disease is spreading rapidly. Several targets have been identified in the search for a treatment against HIV infection, but until now only three have been successfully spotted. They correspond to two fundamental enzymes for the virus life cycle (protease (PR) and reverse transcriptase (RT)) and very recently to the event of membrane fusion between the virus and the cell. FDA has approved a total of twenty five antiretrovirals, nine of which targeting PR, fifteen RT and one targeting virus entry. Additionally, albeit in the early stages of clinical trials, there are also inhibitors being developed against the viral enzyme integrase (IN). This work deals with the inhibition of PR. This enzyme has been considered as a paradigm of success in structure based drug design, and there are more three-dimensional structures resolved for PR than for any other enzyme. The catalytic mechanism is briefly outlined. Subsequently, the rational development of PR inhibitors is discussed, the existing data for the currently in vitro and in vivo efficient compounds are compiled, and the methodologies to improve their potency and bioavailability are explained.