The long-term usage of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) eventually leads to rapid emergence of drug-resistant viruses and severe side effect. Therefore, it is imperative to seek the additional NNRTIs with potent and broad spectrum anti-mutant activities, and excellent pharmacokinetic profiles. The discovery of etravirine, rilpivirine and other successful examples has influenced the NNRTIs design strategy profoundly. Sustained efforts in this area have led to the identification of many promising NNRTIs hits, leads and candidates for the last few years. Hence, this review aims to highlight recent prominent advances in this field as well as contributions from our laboratory toward the discovery of novel potent NNRTIs from 2009 to 2013 (by May).