Cell migration is a fundamental process, playing a central role in embryonic development, wound healing, inflammation, and tumor metastasis. To migrate, cells must form a leading and trailing edge, apply coordinated force in the direction of movement, and both adhere and release their hold on the substrate as they travel (1–5). To perform these feats, migrating cells respond to a variety of factors such as extracellular matrix molecules and growth factors, which engage cell surface receptors to initiate and maintain migration. One such family of receptors, the integrins, plays an important role in migration, in part by adhering to the extracellular matrix, and activating intracellular cascades that promote actin polymerization involved in lamellipodial extension (1–5). Integrins are heterodimeric receptors that consist of α- and β-subunits with large extracellular ligand-binding domains, and smaller cytoplasmic domains that initiate intracellular signaling (1–5). One mechanism of integrin-mediated cell migration involves the ability of integrins to regulate the activity of the Rho family of small G proteins. For example, localized Rac activation, important for lamellipodial extension, is promoted at the leading edge of cells by α4β1 integrin phosphorylation and consequent unbinding of the signaling adapter protein paxillin and is inhibited at the trailing edge by α4β1 dephosphorylation, binding of paxillin, and inactivation of Rac (1, 4). The closely related α9β1 integrin also is able to enhance cell migration, but its mechanism of action was not known. In an elegant study from the Sheppard laboratory published in this issue of PNAS (6), deHart et al. identify a novel pathway by which α9β1 integrins increase cell migration by modulation of polyamine metabolism and activation of potassium channels.