Matrix Extracellular Phosphoglycoprotein (MEPE) belongs to a group of proteins called Short Integrin Binding Ligand Interacting Glycoproteins (SIBLINGs). These proteins are all localized to a defined region on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of SIBLING proteins is an Acidic Serine Aspartate Rich MEPE associated motif (ASARM). The ASARM-motif and SIBLINGs appeared 300 million years ago with terrestrial vertebrates coincident with the new environmental challenge of gravity. Recent research has shown that the ASARM-motif and the released ASARM-peptide also play regulatory roles in mineralization (bone and teeth), phosphate regulation, vascularization, soft tissue calcification, osteoclastogenesis, mechanotransduction and fat energy metabolism. The MEPE ASARM-motif and peptide are physiological substrates for PHEX, a Zn metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another ASARM-motif containing SIBLING protein, Dentin Matrix Protein-1 (DMP1). DMP1 mutations cause bone-renal defects that are identical with the defects caused by loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both HYP and ARHR increased FGF23 expression occurs and activating mutations in FGF23 cause autosomal dominant hypophosphatemic rickets (ADHR). ASARMpeptide administration in vitro and in vivo also induces increased FGF23 expression. Recent work indicates a competitive displacement of a PHEX DMP1 interaction by ASARM-peptide and thus increased FGF23 expression.