Since the discovery of the human immunodeficiency virus type 1 (HIV-1) as the causative agent of AIDS in the early eighties, its spread has been dramatic. Current therapeutic strategies for the inhibition of viral replication employ a combination of drugs targeted at the viral reverse transcriptase and protease enzymes. The clinical benefit of this combination therapy is considerable, although often only transient, partly due to the emergence of multiple drug-resistant viral strains. The addition of new anti-HIV drugs targeting a third step of the viral replication may help in preventing resistance development. During HIV replication, the integration of the genome into the cellular chromosome is a vital step, which is catalysed by the viral integrase. The search for antiviral compounds capable of selective inhibition of integrase during viral replication is laborious and the large-scale screening programs for integrase inhibitors have thus far led to only one series of compounds that selectively inhibit the integration step of HIV replication, the diketo acids. In this review we summarize the current knowledge about HIV-1 integrase and integrase inhibitors. We address the issue why it is so difficult to find potent and selective integrase inhibitors, suitable to be included in a therapeutic drug combination and we propose new strategies for the discovery of integration inhibitors.