Human IGFBP-4 was initially cloned from the human placenta, liver, and ovary cDNA libraries. Seven IGFBPs has been described that modulate the IGF activity. IGFBPs structurally are characterized by three domains: the amino-terminal, the carboxyl-terminal, and an intermediate variable L-domain. Some IGFBPs bind to the extracellular matrix (IGFBP-2, -3, and -5) or the cell membrane (IGFBP-1, -2, -3, and -5). The IGF binding activity of IGFBP-4 is mainly localized in the N-terminal region. IGFBP-4 is the smallest IGFBP, and there is no evidence for cell surface or ECM association of IGFBP-4. In addition, it contains an N-linked glycosylation site and exists in biological fluids as a doublet of 24 kD nonglycosylated and a 28 kD glycosylated forms. IGFBP-4 binds both IGF-I and IGF-II with similar affinities. Nevertheless, it is generally coexpressed with IGF-II during development. Proteolysis is the main regulatory mechanism of IGFBP-4 activity. Pregnancy-associated plasma protein-A (PAPP-A) was identified as an IGF-dependent IGFBP-4 protease. It belongs to the metzincin superfamily of metalloproteinases and cleaves IGFBP-4 at a single site. IGFBP-4 has potent IGF-independent anti-angiogenic and antitumorigenic effects, activities that are located in the C-terminal, and a region containing a thyroglobulin type 1 (Tg1) domain.