Abstract: As the second leading cause of death worldwide, cancer is one of the major public health problems. The emergence and extensive utilization of small molecule targeted anti-cancer drugs have led to substantial improvements in the cure rate of cancer and the survival of patients. However, the subsequent problem of drug resistance arises, with a significant proportion of small molecule targeted anti-cancer drugs showing varying levels of resistance after a duration of administration.Investigating the mechanism underlying drug resistance is essential for identifying effective strategies to overcome the resistance in small molecule targeted anti-cancer therapies.This review provides a comprehensive summary of the prevailing drug resistance mechanisms reported in small molecule targeted anticancer therapies. Additionally, strategies to overcome drug resistance are proposed, thereby offering valuable references for further drug development efforts.