The retroviruses are a large, diverse family of enveloped RNA viruses defined by their structure, composition and replicative properties. The hallmark of the family is its replicative strategy, essential steps of which include reverse transcription of the viral RNA and the subsequent integration of this DNA into the genome of the cell. These steps are performed by two viral-encoded enzymes, reverse transcriptase (RT), which possesses DNA polymerase and ribonuclease H (RNase H) activities, and integrase (IN). These enzymes are excellent targets for retroviral therapy since they are essential for viral replication. Numerous substances capable of inhibiting the DNA polymerase activity of HIV-1 RT are available, while few specific inhibitors of RNase H activity have been described. IN is absolutely necessary for stable and productive infection of cells. Some IN inhibitors have been recently reported and are available demonstrating the potential of IN as an antiviral target. This paper is an overview of the inhibitors of RNase H and IN and describes the most promising inhibitors.