Directional migration is a critical component of cell motility is observed in many diverse processes including embryogenesis, immune surveillance and wound repair. A central aspect of directional migration is cellular polarity, which is established through several signaling pathways that converge on the small GTPases. These factors orchestrate precise spatial and temporal organization of the actin cytoskeleton at the leading edge of the cell, and induce polarized capture and stabilization of microtubules and their associated microtubule organizing center (MTOC). Studies of the regulation of the GTPases have predominantly focused on posttranslational mechanisms involving guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). In this commentary, we examine the transcriptional regulation of these factors, focusing on the recently described regulation of RhoGEF19, an activator of RhoA, by the epidermal-specific transcription factor GRHL3, and the importance of this regulatory mechanism in wound repair. Our findings establish novel links between epidermal cell migration in wound healing and the planar cell polarity (PCP) signaling pathway, and establish a paradigm for tissue-specific regulation of Rho GTPase activity. A? 2010 Landes Bioscience.