Human Immunodeficiency Virus Reverse Transcriptase (HIV-1RT), catalysing synthesis of proviral cDNA has been widely exploited as a most suitable target for attack by anti-AIDS chemotherapeutics. The antiHIV-1RT molecules involve dideoxy analogues of dNTP (nucleoside reverse transcriptase inhibitors, NRTIs), which inhibit it competitively by terminating DNA chain extension. The other group of HIV-1 RT inhibitors involves non-nucleoside reverse transcriptase inhibitors (NNRTIs), which bind preferably in the hydrophobic pocket or elsewhere at enzyme surface, inhibit it non-competitively. The AIDS therapy prescribes different combinations of various anti-HIV drugs mainly the antiHIV-1RTs and antiproteases (in highly active antiretroviral therapy; HAART), which significantly reduces HIV count to undetectable level. Unfortunately, due to drug selection pressure drug resistant variants of HIV-1 emerge and preclude chemotherapy of this pandemic. This paper is an endeavour to illustrate possible mechanisms involved in anti-HIV drugs resistance. Apart from attributes of numerous mutations reported in three key enzymes of HIV (RT, protease and integrase) in making antiHIV drugs, one plausible mechanism of nucleoside analogue resistance involves ATP/GTP-based excision to unblock chain-terminated primers; thereby allowing viral replication to continue. Such unblocking has also been reported in vitro in presence of excess of pyrophosphate concentration; a reaction known as pyrophosphorolysis. In addition to viral mutants isolated from the AIDS patients, we have shown some artificial mutants of K154, which exhibited antiHIV-1 drugs resistance property and the mechanism involved reduction in binding of the drugs to RT because of conformational change. Our recent report on mechanism of resistance of HIV-1RT against rilpivirin due to E138K mutation proposes a new aspect in this context. However, an extensive study exploring some new targets and drug resistance mechanisms is needed for design and development of novel and potential anti-viral agents to combat this challenge