Nature represents a rich source of compounds used for the treatment of many diseases. Camptothecin (CPT), isolated from the bark of Camptotheca acuminata, is a cytotoxic alkaloid that attenuates cancer cell replication by inhibiting DNA topoisomerase 1. Despite its promising and wide spectrum antiproliferative activity, its use is limited due to low solubility, instability, acquired tumour cell resistance, and remarkable toxicity. This has led to the development of numerous CPT analogues with improved pharmacodynamic and pharmacokinetic profiles. Three natural product-inspired drugs, namely, topotecan, irinotecan, and belotecan, are clinically approved and prescribed drugs for the treatment of several types of cancer, whereas other derivatives are in clinical trials. In this review, which covers literature from 2015 to 2020, we aim to provide a comprehensive overview and describe efforts that led to the development of a variety of CPT analogues. These efforts have led to the discovery of potent, first-in-class chemotherapeutic agents inspired by CPT. In addition, the mechanism of action, SAR studies, and recent advances of novel CPT drug delivery systems and antibody drug conjugates are discussed.