The NNRTIs play an important role in the present therapy against HIV/AIDS. This review discusses the basic principles in the development of NNRTIs for HIV therapy. It also summarizes the NNRTIs in clinical use and the major series of NNRTIs in development phases. The authors intend to provide an overview of the NNRTI research and to elucidate some important factors in directing the future in the field such as genetic barrier, QD dosing, safety profile and combination with other anti-HIV agents. Despite the enormous progress that has been achieved in the NNRTI field in the past two decades, the present clinical pipeline appears to be insufficient to tackle the huge medical need. The efforts of finding new NNRTIs are certainly much motivated and can be highly rewarding.