Lysophosphatidic acid (LPA) enhances cell motility in many cell types and is thought to promote metastasis as well as wound repair. LPA is well known to elicit mobilization of intracellular calcium ([Ca²⁺]_i) but the physiological consequences downstream of this phenomenon remain incompletely explored. Here we tested the wound healing-related hypothesis that LPA-activated calcium fluxes affect the motility of normal human epidermal keratinocytes through the calcium-responsive NFAT signalling pathway. Moreover, we characterized LPA-evoked calcium mobilization, investigating if LPA-induced calcium signalling was modulated by the extracellular calcium concentration [Ca²⁺]_o and analyzing the involvement of Orai1 channels and lipid rafts. The effect of LPA on keratinocyte migration was assessed over 14h using a 2-dimensional wounding motility assay and a 3-dimensional chemotactic migration assay. As expected, 10 µM LPA significantly promoted both 2- and 3-dimensional cell migration. Pre-treatment for 1h with the NFAT pathway inhibitor cyclosporin A (CsA, 1 µM) significantly impaired LPA-induced migration, indicating that LPA induces keratinocyte migration through the NFAT pathway. As monitored by Fluo-4 imaging, LPA stimulation of keratinocytes in 60 µM [Ca²⁺]_o evoked short-lived (±3 min) transient [Ca²⁺]_i elevations due to store release, while in 1.2 mM [Ca²⁺]_o, LPA triggered a peak elevation of [Ca²⁺]_i followed by a plateau elevation extending over 10 min, indicating store release coupled to extracellular calcium influx. As expected, manganese quenching blocked calcium influx. Interestingly, calcium influx was blocked by diethylstilbestrol (DES) but not by the SK&F96365 or MRS-1845. Transient expression of dominant/negative Orai1^R91W and lipid raft disruption using methyl-β-cyclodextrin treatment also impaired LPA-evoked calcium entry. NFAT activity was assessed using a luciferase reporter assay and by monitoring the nuclear translocation of GFP-tagged NFAT2. Both assays revealed modest activation of NFAT by LPA-evoked store release. LPA-evoked store release coupled to influx in 1.2 mM [Ca²⁺]_o resulted in a much more robust activation of NFAT, which was blocked by addition of DES, expression of mutant Orai1^R91W and lipid raft disruption. Our data thus indicate that LPA promotes keratinocyte migration by triggering [Ca²⁺]_i influx, which activates a NFAT signalling cascade via Orai1 and lipid rafts, firstly suggesting an involvement of NFAT in epidermal wound healing.