In advanced breast carcinomas, the α6β4 integrin is associated with a migratory and invasive phenotype. In our current study, we show that expression of the α6β4 integrin in MDA-MB-435 breast carcinoma cells leads to increased expression of the autocrine motility factor autotaxin, as determined by Affymetrix gene chip, real-time quantitative RT–PCR and immunoblot analyses. We further demonstrate that increased autotaxin secretion from integrin α6β4 expressing cells acts to enhance chemotaxis through its ability to convert lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA) and accounts for 80% of the motogenic activity of the conditioned medium. We determine that integrin α6β4-dependent overexpression of autotaxin in MDA-MB-435 cells is mediated by NFAT1, but not NFAT5, through the use of siRNAs that specifically target autotaxin, integrin β4, NFAT1 and NFAT5. Finally, we show by electrophoretic mobility shift assays that two consensus NFAT binding sites found in the autotaxin promoter strongly and specifically bind NFAT1 from integrin α6β4 expressing cells. In summary, we find that the α6β4 integrin potentiates autotaxin expression through the upregulation and activation of NFAT1. These observations highlight for the first time a mechanism by which NFAT transcription factors can facilitate an invasive and motile phenotype downstream of integrin α6β4 signaling.