Efficient DNA repair is critical for cell survival following exposure to DNA topoisomerase I (Top1) inhibitors camptothecin, a nature product from which the common chemotherapeutic drugs irinotecan and topotecan are derived. The camptothecin-derived agents exert their antitumor activities by specifically stabilizing the Top1–DNA covalent complexes (Top1cc) and blocking the DNA religation step. When exposed to these DNA damage agents, tumor cells quickly activate DNA damage response. This allows sufficient time to remove the Top1ccs and prevent tumor cells from apoptosis. Several repair pathways have been implicated in this process. One of the most relevant repair modes is DNA single strand break repair (SSBR) pathway. The expression level or mutagenesis of specific repair factors involved in SSBR pathway may play an indispensable role in individual’s capacity of repairing camptothecin induced DNA damage. Therefore, understanding of the tolerance pathways counteracted to camptothecin cytotoxicity is crucial in alleviating chemotherapy resistance. This review focus on the SSBR pathway in repair camptothecin induced DNA damage, aiming to provide insights into the potential molecular determinants of camptothecin chemosensitivity.