HIV RNase H is one particular story target and, in the last couple of years, significant progress is made in distinguishing and characterizing new RNase H inhibitor pharmacophores. Within this review we focus mainly on the absolute most powerful low micromolar efficiency compounds, as these provide bases for further growth. We also discuss why HIV Linifanib FLT-3 inhibitor RNase H is a huge difficult target for anti-retroviral drug development. The viral enzyme reverse transcriptase is essential for replication of the human immunodeficiency virus, the causative agent of acquired immunodeficiency syndrome. HIV RT is multi-functional, with both RNA dependent and DNAdependent DNA polymerase activity, in addition to ribonuclease H activity that degrades the RNA element of the RNA/DNA hybrids duplex intermediate formed throughout reverse transcription. All of these RT activities are crucial for transformation of the viral single strand genomic RNA into double strand DNA that may then be integrated into the host cell genome. HIV RT is different somewhat from cellular DNA polymerases and it’s become a major target for anti-viral drug discovery and development. In mid 2012 over half the FDAapproved hematopoietin drugs or drug combinations for the treatment of AIDS/HIV comprise inhibitors of RT DNA polymerase activity. These inhibitors comprise two different classes, nonnucleoside RT inhibitors and nucleoside/ nucleotide RT inhibitors RTIs), different in structure and mechanism of action. NRTIs are RT active site directed nucleoside analogs that need metabolic activation for antiviral activity. Once triggered, NtRTI diphosphates and NRTI triphosphates take on cellular deoxynucleotides for binding to the RT polymerase active site. Further viral DNA synthesis is blocked and more importantly, NRTIs lack a 3 OH hydroxyl on the sugar analogue moiety of the drug, thus once incorporated by RT into the viral DNA, selective c-Met inhibitor extension is avoided. In comparison, NNRTIs comprise a diverse number of chemical components that bind to an allosteric site on RT different from the polymerase active site, and do not require metabolic activation for antiviral activity. NNRTIs are non-competitive with respect to deoxynucleotide substrates and are thought to prevent RT catalyzed DNA polymerization by causing conformational changes that alter RT active site geometry. But, the quick mutation rate of HIV has led to the growth of resistance to each of the clinically used antiretrovirals as well as viral variants with variable class drug resistance, potentially impacting to the ongoing efficacy of current drug regimens. Confirmed underexplored steps of HIV replication ongoing drug discovery and development is essential, especially drugs inclined to. HIV RT connected RNase H activity is one such goal. Appropriately, HIV has received increased attention in the last decade.