Chemoprevention represents one of the most highly effective anti-cancer strategies and is accompanied by minimal secondary effects as compared to conventional chemotherapies. Many new anti-inflammatory and anti-cancer drug candidates have been derived from chemical scaffolds engineered from natural products discovered just a few decades ago. This approach is widely utilized in drug discovery in order to produce novel molecular entities with enhanced drug activities mediated through various signal transduction pathways for the treatment of different diseases. Curcumin, a polyphenolic derivative of turmeric, is a naturally occurring compound isolated from Curcuma longa that suppresses and inverts carcinogenesis via multifaceted molecular targets. Several reports have demonstrated that curcumin inhibits animal and human cancers, suggesting that it may serve as a chemopreventive agent. Numerous in vitro and in vivo experimental models have also revealed that curcumin regulates several molecules in cell signal transduction pathway including NF-κB, Akt, MAPK, p53, Nrf2, Notch-1, JAK/STAT, β-catenin, and AMPK. Modulation of cell signaling pathways through the pleiotropic effects of curcumin likely activate cell death signals and induce apoptosis in cancer cells, thereby inhibiting the progression of disease. This article provides insights into the natural chemopreventive role of curcumin via cellular transduction pathways and provides an in depth assessment of its physiological activities in the management of diseases.