Early studies in the IGF/IGF-IR-independent actions of IGFBP-3 have been shown that IGFBP-3 binding to a cell surface protein is required for its anti-proliferative action in human breast cancer cells and that the central domain of IGFBP-3, which is the least conserved region among IGFBPs 1–6, is responsible for cell surface binding [33,70,105]. The gene discussed is IGFBP3; the disease is breast cancer.