Current strategies for the treatment of HIV infection are based on cocktails of drugs that target the viral reverse transcriptase or protease enzymes. At present, the clinical benefit of this combination therapy for HIV-infected patients is considerable, although it is not clear how long this effect will last taking into account the emergence of multiple drug-resistant viral strains. Addition of new anti-HIV drugs targeting additional steps of the viral replication cycle may increase the potency of inhibition and prevent resistance development. During HIV replication, integration of the viral genome into the cellular chromosome is an essential step catalysed by the viral integrase. Although HIV integrase is an attractive target for antiviral therapy, so far all research efforts have led to the identification of only one series of compounds that selectively inhibit the integration step during HIV replication, namely the diketo acids. In this review we try to address the question why it has proven so difficult to find potent and selective integrase inhibitors. We point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor, and propose new strategies and technologies for the discovery of authentic HIV integration inhibitors.