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Cancer remains a significant global health challenge, with an estimated 20 million new cases and 9.7 million deaths reported worldwide in 2022, and projections indicating a surge to 35 million cases by 2050. This epidemic necessitates innovative approaches to treatment development. This chapter examines the critical role of natural products in anticancer drug discovery, highlighting the natural products’ contribution to currently used anticancer treatments. Approximately 40% of current pharmaceutical products are derived from natural sources, with significant contributions to cancer therapeutics. Notable examples include plant-derived compounds, such as vinca alkaloids, taxanes, podophyllotoxin derivatives, and camptothecin derivatives, which have proven highly effective in various cancer treatments. Additionally, microorganisms from soil samples and marine environments have yielded potent antitumor antibiotics and antimitotic agents. Despite challenges in sustainable sourcing and complex manufacturing processes, advances in high-throughput screening, metabolomics, metagenomics, and synthetic biology are enabling more systematic exploration of nature’s chemical diversity. This chapter emphasizes the importance of preserving traditional knowledge systems and expanding cross-disciplinary collaboration to harness Earth’s remarkable biodiversity as an untapped reservoir of potentially transformative chemotherapeutic agents in the ongoing fight against cancer.