Recent findings slggest that cellular activity and mineral chemistry have important roles in initiating mineral formation in calcifying tissues. Under biological conditions, hydroxyapatite (HA), the predominant and most stable form of insoluble calcium phosphate, forms only through a more soluble, noncrystalline precursor, amorphous calcium phosphate (ACP). The conversion of ACP to HA can be extensively inhibited by many biologically ubiquitous small ions at their typical tissue concentrations. The earliest mineral deposits in the matrix of several calcifying tissues are associated with tiny membranous vesicles. Intramitochondrial calcium phosphate granules are also seen within intact cells of certain calcifying tissues. Current hypotheses for initial mineral deposition, based on these findings, are reviewed.