Calcium regulates the proliferation and differentiation of keratinocytes both in vivo and in vitro. Elevated extracellular Ca2+ concentration ([Ca2+](o)) raises the intracellular free calcium ([Ca2+](i)) and activates differentiation-related genes. Cells lacking the calcium-sensing receptor (CaR) fail to respond to [Ca2+](o) and to differentiate, indicating a role for CaR in keratinocyte differentiation. These concepts derived from in vitro experiments have been tested and confirmed in two mouse models. (C) 2003 Elsevier Ltd. All rights reserved.