Camptothecin is one of the human success stories in the history of drug discovery from natural resources. In this mini-review, the painstaking efforts of eminent scientists of different disciplines to isolate and identify camptothecin as active anticancer compound from Camptotheca acuminata are narrated. Due course, the unique mode of action of camptothecin was discovered. Clinically some tumors acquire de novo resistance to camptothecin and a few of molecular mechanisms responsible for clinical resistance are discussed in brief. Finally, we discuss novel sources and how biotechnological methods are utilized for a sustainable production of camptothecin without impacting the natural flora.