Myelodysplastic syndrome (MDS) consists of a group of heterogeneous clonal myeloid stem cell diseases characterized by pancytopenia and high-risk of transformation to acute myeloid leukemia (AML). At present, the hypomethylating agents (HMA) are widely used in the treatment of MDS, which show good therapeutic effects in clinical trials and practical applications, but the phenomenon of HMA resistance is almost universal, and the prognosis of patients with HMA resistance is often poor.This article explains the advance on mechanisms of HMA, and the resistance mechanisms of HMA which include the drug metabolism factors that affect HMA, the up-regulation expression of immune checkpoint pathway (ICP), and the imcompletely eliminate of leukemia stem/progenitor cells (LSPC), in order to explore the possible mechanisms and solutions methods of HMA resistance in MDS patients.