Herbicide safeners are a series of agrochemicals that can selectively protect crop plants from herbicide injury without affecting herbicidal efficacy. Understanding mechanisms by which safeners act is significant for discovery of novel types. Safeners primarily alleviate herbicide phytotoxicity to crop plants via several actions: (i) enhancing metabolism of herbicides in crops; (ii) affecting absorption and transportation of herbicides in crops; (iii) competitively binding to herbicide target sites; and (iv) affecting activity of target enzymes. This review describes recent advances in the action mechanisms of safeners, analyzes existing problems, anticipates the future direction of studies of modes of action of safeners, and prospects potential strategies to design safeners related to their reported mechanisms. The aim of this paper is to provide insight into mechanisms of safeners and give tips for development of new safeners.