Abstract: Mismatch repair system (MMR) is an important post-replication repair mechanisms and repairs various types of base mismatch and insertion/deletion loop. HMutS, hMutL are two important subsystems of the MMR. Their function defects associate with a variety of tumors, especially colorectal cancer. SNPs and promoter methylation level of key genes in hMutS, hMutL system would directly or indirectly affect the MMR function, further to increase microsatellite instability, and play an important role in the occurrence, development and prognosis of colorectal cancer. This article briefly reviewed the research progress on the relationship between key genes variation in hMutS, hMutL and colorectal cancer from SNPs, promoter methylation level and microsatellite instability.