Mineralization of bone involves secretion of extracellular matrix (ECM) and associated molecules by specialized cells termed osteoblasts. Key proteins in this process include collagen I and alkaline phosphatase (ALP), which promotes mineralization by breaking down pyrophosphate. How mineralization is regulated has been unclear, but Jennifer Gillette and Sheila Nielsen-Preiss now show that annexin 2 – one of a family of proteins implicated in membrane trafficking and signalling – plays a part. Having picked out annexin 2 in a screen for genes expressed in bone malignancies, the authors show that its expression increases ALP activity in osteoblasts and promotes mineralization whereas antisense annexin 2 oligonucleotides inhibit this (see p. 441). Annexin 2 does not stimulate synthesis of ALP. However, Gillette and Nielsen-Preiss notice that annexin 2 and ALP both localize to lipid rafts (ordered plasma membrane microdomains) and that overexpression of annexin 2 increases raft-associated ALP activity. Furthermore, they find that cholesterol-sequestering agents that disrupt rafts reduce both mineralization and ALP activity. Annexin 2 thus appears to regulate the organization of ALP-containing lipid rafts in osteoblasts. The authors propose that it promotes their coalescence, which could activate ALP directly and/or stimulate signalling cascades that target it.