Colorectal cancer(CRC)ranks the third in incidence and mortality rate among human tumors. Tumor relapse,me?tastasis and drug resistance remain the main obstacle to the success of CRC treatments. Compared to traditional chemotherapy ,target therapy seems to treat tumors in more precise and rational fashion with good response and often less toxic side-effect. Although target agents provide hope for more effective therapy,recent clinical studies have shown only modest benefit from target therapy similar to tra?ditional chemotherapy. Primary and secondary resistance to target agents is still observed and contributes to CRC treatment failure. The review summarizes research progress in the mechanism of drug resistance to target therapy in CRC treatment.