The diverse nature of chemotherapeutic agents obtained from natural compounds has led to the uncovering of several novel anti-cancer mechanisms, which are crucial for their spectrum of activity. Alkaloids are a class of organic compounds that have contributed to developing drugs used to treat a wide array of illnesses. Several alkaloids extracted from natural sources have demonstrated anti-cancer properties against various types of cancer when tested using cell culture, preclinical, and clinical studies. Chemotherapeutic compounds obtained and synthesized from natural sources of alkaloids might be the best possible solution for reducing the harmful side effects of currently utilized anti-cancer products. The chapter provides a thorough and critical assessment of naturally occurring alkaloids with anti-cancer properties and an overview of some of the alkaloid-containing natural compounds that have demonstrated significant anti-proliferative activity and progressed to preclinical and/or clinical trials in the context of future drug development for cancer therapy.