Our laboratory has been investigating the functions of store-operated Ca2+ entry (SOCE) in various physiological contexts by a combined strategy employing cell lines together with genetically modified mouse models. We disclosed significant roles for store-operated channels in the development and function of bone cells, both osteoclasts and osteoblasts; in lacrimal gland function; in differentiation of keratinocytes as well as in their role in wound healing. In this presentation, I will discuss our recent work on the role of store-operated Ca2+ channels in chemotaxing neutrophils. Chemotaxis is essential for neutrophils to locate sites of inflammation. The formylated chemotactic peptide, fMLF, is an agonist for FRPR1 receptors through which it activates phospholipase C and induces Ca2+ release from intracellular endoplasmic reticulum stores. We first investigated the Ca2+ dependence of chemotaxis in the differentiated HL-60 cell model. Using a transwell assay, we determined that chemotaxis, but not undirected movement, is completely lost in the absence of extracellular Ca2+ or in the presence of the SOCE inhibitor, Gd3+. In many cell types, STIM1, a Ca2+ sensor protein resident in the endoplasmic reticulum, detects the extent of Ca2+ depletion and communicates this to plasma membrane Orai calcium channels to activate SOCE. In addition, STIM1 is known to play a role in organizing the organellar structure of cells through an interaction with the microtubule network. Down regulation by siRNA of STIM1 or its channel partner, Orai1, revealed that both proteins are required for chemotaxis. We over-expressed an eYFP-tagged STIM1, which augmented fMLF-induced Ca2+ signaling, as well as fMLF-induced chemotaxis. We followed the localization of eYFP-STIM1 by confocal microscopy. Chemotaxing cells polarize and move in a crawling way to a target which in this study was a micro-pipette releasing fMLF. During chemotaxis, STIM1 cellular localization was not homogeneous but rather STIM1 accumulated in the rear of migrating cells, the uropode. We analyzed the effect of STIM1 knock out in neutrophils, in vivo, in a conditional STIM1fl/fl LyzM+/+ knockout mouse model. Treatment of mice with imiquimod cream induced a psoriasis-like skin condition and induced neutrophil migration into the skin. STIM1fl/fl LyzM+/+ knockout mice had significantly less infiltrated neutrophils in the epidermis than control mice. Together, our results suggest that Ca2+ signaling, involving SOCE, is necessary for chemotaxis in vitro and in vivo. STIM1, and by inference SOCE, may play a role in the spatiotemporal dynamics of the uropode. These findings provide new insights to our understanding of how intracellular Ca2+ changes orchestrate the cellular behavior underlying chemotactic directional movement.