The Insulin-like Growth Factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. IGFBP-3 is the most abundant IGF binding protein in human serum and has been shown to be a growth inhibitory, apoptosis-inducing molecule, capable of acting via IGF-dependent and IGF-independent mechanisms. Over the last decade, several clinical studies have proposed that individuals with IGFBP-3 levels in the upper range of normal may have a decreased risk for certain common cancers. This includes evidence of a protective effect against breast cancer, prostate cancer, colorectal cancer, and lung cancer. In addition, a series of in vitro studies and animal experiments point towards an important role for IGFBP-3 in the regulation of cell growth and apoptosis. In this brief review, we discuss the biological role of IGFBP-3 and summarize the epidemiological and experimental evidence suggesting a role for IGFBP-3 as an anti-cancer molecule.