Eradication of human immunodeficiency virus (HIV) from infected cells or organisms has remained an elusive goal. In principle, any of the steps in the replicative cycle could form the basis for rational design of chemotherapeutic agents, although in practice not all have so far proved amenable to intervention. Here, Erik De Clercq summarizes the strategies that are being employed, focusing primarily on recent promising developments in inhibition of adsorption of HIV onto CD4+ T cells, and inhibition of the viral reverse transcriptase.