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Saponins are bioactive compounds produced mainly by plants but also by some marine organisms and insects. In the recent past, there has been unforeseen interest in the clinical utilization of saponins as chemotherapeutic agents. The research on saponins in various forms as a treatment for cancer has generated a lot of potential. The advent of nanotechnology and the cytotoxicity enhancing properties of saponins are some of the highlights of the current decade. This review gives an updated overview of the clinical potential that saponins hold as cytotoxic agents, and covers the literature for 1957–2011, with the main focus on research conducted in the last decade. It is conceivable that saponins hold a lot of therapeutic potential and could be a lead for identification of synthetic or semisynthetic molecules for the treatment of cancer via membrane-mediated or transport-mediated pathways.