Curcumin is a major constituent of the turmeric plant Curcuma longa, a member of the Zingiberaceae family, which is cultivated in India, most parts of Southeast Asia, Asia and other parts of the world. Curcumin has been shown to afford a wide range of pharmacological activities encompassing antioxidative, anti-inflammatory, antibacterial, antifungal, antiviral, antiproliferative, proapoptotic and anti-atherosclerotic effects as well as medicinal benefits against neurodegenerative diseases, arthritis, allergy, inflammatory bowel disease, nephrotoxicity, AIDS, psoriasis, diabetes, multiple sclerosis, cardiovascular disease and lung fibrosis. Moreover, curcumin could suppress inflammatory cytokines as well as suppress various target proteins in cancer cell lines. Owing to its multi-faceted health benefits, curcumin has been used as health supplements as well as natural remedy while several clinical trials are under way to investigate its potential therapeutic usage. This chapter discusses the origins of curcumin’s biological activities in light of its structure-activity relationship. The structure of curcumin is comprised of the central 1,6-heptadiene-3,5-dione bearing two terminal phenolic rings. Structural modification of this compound alters its biological activities either by affecting its selectivity, specificity or potency. Understanding of such structure-activity relationship may provide the impetus for further expanding its biological activity repertoire. Although it is an ambitious task to review the current state-of-the-art on the structure-activity relationship of curcumin, it should be mentioned that it is impossible for this chapter to provide a comprehensive account but rather a representative overview is given herein.