The article reviews the advancements, challenges, and future perspectives of small-molecule targeted cancer therapies. Since the approval of the first tyrosine kinase inhibitor, imatinib, in 2001, numerous small-molecule targeted drugs have been developed for cancer treatment. By December 2020, 89 such drugs had been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite these advancements, challenges such as low response rates and drug resistance persist. The review categorizes small-molecule targeted anti-cancer drugs by their targets and presents all approved drugs and important candidates in clinical trials. It discusses current challenges and provides insights for future research and development. Key targets include kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes. The article also highlights the development of ALK inhibitors, c-Met inhibitors, EGFR inhibitors, FLT3 inhibitors, and VEGFR/FGR/PDGFR inhibitors, detailing their mechanisms, clinical applications, and resistance mechanisms.The article reviews the advancements, challenges, and future perspectives of small-molecule targeted cancer therapies. Since the approval of the first tyrosine kinase inhibitor, imatinib, in 2001, numerous small-molecule targeted drugs have been developed for cancer treatment. By December 2020, 89 such drugs had been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite these advancements, challenges such as low response rates and drug resistance persist. The review categorizes small-molecule targeted anti-cancer drugs by their targets and presents all approved drugs and important candidates in clinical trials. It discusses current challenges and provides insights for future research and development. Key targets include kinases, epigenetic regulatory proteins, DNA damage repair enzymes, and proteasomes. The article also highlights the development of ALK inhibitors, c-Met inhibitors, EGFR inhibitors, FLT3 inhibitors, and VEGFR/FGR/PDGFR inhibitors, detailing their mechanisms, clinical applications, and resistance mechanisms.