HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.