HIV infection is the leading cause of death worldwide and despite major advances in treatment, more new cases were diagnosed in 2004 than any previous year. Current treatment regimens are based on the use of two or more drugs from two or more classes of inhibitors termed highly active antiretroviral therapy (HAART). Although HAART is capable of suppressing viral loads to undetectable levels, problems of toxicity, patient adherence, and particularly the emergence of drug-resistant viruses continues to spur the development of new chemotherapeutics to combat HIV. Clinical candidates from the four existing classes of inhibitors are presented in this review along with lead compounds against new viral targets, with special emphasis on HIV integrase.