Abstract: Abnormal function of protein kinases has been closely related to tumors and thus, the development of corresponding protein kinase inhibitors to regulate the relevant signal transduction pathways is the current focus of anti-tumor drug development research. Since the first protein kinase inhibitor was licensed by the FDA in 2001, more than 50 protein kinase inhibitors have been approved for the treatment of malignant tumors such as breast and lung cancers, playing important roles in cancertreatment. However, small molecule kinase inhibitors also have several issues that need to be addressed. Hence, researchers continue to develop new kinase-targeting drugs to resolve these issues. Nevertheless, many new small molecule kinase inhibitors are being tested in clinical trials. This review summarizes the classification, substrates, and anti-tumor mechanisms of small molecule protein kinase inhibitors. Moreover, the advances in research and trends in the development of anti-tumor small molecule kinase inhibitors have been described systematically.