Despite the wealth of information available for the reverse transcriptase (RT)-associated ribonuclease H (RNaseH) domain of lentiviruses, gammaretroviruses and long terminal repeat containing retrotransposons, exploiting this information in the form of an RNaseH inhibitor with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that the two-subunit HIV-1 RT is a highly versatile enzyme, undergoing major structural alterations in order to interact with, position and ultimately hydrolyze the RNA component of an RNA/DNA hybrid. Thus, in addition to targeting the RNaseH active site, identifying small molecules that bind elsewhere and disrupt catalysis allosterically by impairing conformational flexibility is gaining increased attention. This review summarizes current progress towards development of both active site and allosteric RNaseH inhibitors.