Abstract: Dihydrofolate reductase(DHFR) is a key enzyme for the synthesis of DNA precursor deoxythymidine(dTMP), which plays an important role in cell proliferation, and is an important target for tumor therapy. Inhibition of DHFR can inhibit dTMP biosynthesis, thereby inhibiting the growth or the appreciation of tumor cells, which shows anti-tumor effect in clinic. In recent years, the neurotoxicity of these drugs has greatly limited its clinical application. Based on this, this paper reviewed the application of DHFR inhibitors in tumor therapy, and introduced the corresponding neurotoxic side effects (drug dose restrictive adverse reaction), to explore the developmentof DHFR inhibitors in tumor therapy and to provide guidance for clinical rational drug use to reduce neurotoxicity.