Phytochemicals have potent antitumor properties and have provided multiple active compounds in the past. Although there is an increasing focus on 'designer' targeted therapeutic anticancer agents, the broad spectrum of activity of natural products across multiple signaling pathways remains inadequately explored. The chemical diversity, structural complexity, affordability, lack of substantial toxic effects and inherent biologic activity of natural products makes them ideal candidates for new therapeutics. Natural products not only disrupt aberrant signaling pathways leading to cancer (i.e., proliferation, deregulation of apoptosis, angiogenesis, invasion and metastasis) but also synergize with chemotherapy and radiotherapy. This review focuses on the mechanism of action of key natural products and promising preclinical data on their efficacy as anticancer agents, as single agents and in combination with standard therapies.