Mouse insulin-like growth factor-binding protein 4, also known as IGFBP-4, was initially cloned from the TC-1 bone marrow stromal cell line. Seven IGFBPs have been described to modulate the IGF activity. IGFBPs are characterized structurally by three domains: the amino-terminal, the carboxi-terminal, and a central L-domain. Some IGFBPs bind to the extracellular matrix (IGFBP-2, IGFBP-3, and IGFBP-5) and/or the cell membrane (IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-5). The IGF binding activity of IGFBP-4 is mainly localized in the N-terminal region. IGFBP-4 is the smallest IGFBP and it has no evidence for cell surface or extracellular matrix association. In addition, it contains an N-linked glycosylation site and exists in biological fluids as a dimer of 24 kD nonglycosylated and a 28 kD glycosylated forms. IGFBP-4 binds both IGF-I and IGF-II with similar affinities. Nevertheless, IGFBP-4 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 anti-tumorigenic effects. These activities are located in the C-terminal, which is a region that contains a thyroglobulin type 1 (Tg1) domain.