Seven IGFBPs have been described to modulate the IGF activity. IGFBPs transport IGFs, which means they may inhibit mitogenesis, differentiation, survival, and other IGF-stimulated events. IGFBPs are structurally characterized by three domains: the amino-terminal, the carboxi-terminal, and a central L-domain. Members of the IGFBP family exhibit 67 - 70% structural homology. The greatest homology among the IGFBPs is in the N- and C-terminal regions. Some IGFBPs bind to the extracellular matrix (IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-6). In fact, a heparin-binding domain (HBD) has been identified in the C-terminal region of these binding proteins. In addition to C-terminal HBD, IGFBP-2 contains a HBD located in the linker region. The arginine glycine aspartic acid (RGD) sequence is present in IGFBP-1 and IGFBP-2. This RGD sequence binds to the αVβ1 integrin. IGFBP-2 has a high affinity for IGF-I/IGF-II. It is the second most abundant circulating IGFBP and is expressed in several mammalian tissues. IGFBP-2 and other IGFBPs stimulate biological responses that are independent of their binding to IGFs. IGFBP-2 levels are associated with reduced adipose tissue mass and improved glucose metabolism both in human and mouse models. The HBD of IGFBP-2 has IGF binding-independent biological activity in the growing skeleton. IGFBP-2 mice have impaired bone formation, reduced trabecular bone volume fraction, altered microarchitecture, and low bone turnover. IGFBP-2 is overexpressed in a wide variety of human malignancies, which include glioma, prostate cancer, lung cancer, colorectal cancer, ovarian cancer, adrenocortical tumor, breast cancer, and leukemia.