β-arrestins are pleiotropic molecules that mediate signal desensitization, G-protein-independent signaling, scaffolding of signaling molecules, and chemotaxis(1). Protease-activated-receptor-2 (PAR-2), a G-protein-coupled receptor, which has been proposed as a therapeutic target for inflammation and cancer, requires the scaffolding function of β-arrestins for ERK1/2 activation and chemotaxis(2-5). We have hypothesized that PAR-2 can trigger specific responses by differential activation of two pathways, one through classic Gαq/Ca2+ signaling and one through β-arrestins, and we hypothesized that the latter involves scaffolding of proteins involved in cell migration and proliferation. Our most recent studies have elucidated 3 different G-protein independent signaling pathways downstream of PAR-2: 1) PAR-2 spatially controls the activity of an actin filament severing protein (cofilin) through the formation of a β-arrestin-dependent scaffolding complex comprised of cofilin and its upstream regulators (LIM Kinase and the phosphatase Chronophin). β-arrestin-dependent cofilin activation is independent of Gαq/Ca2+ signaling and is essential for directed cell migration. 2) PAR-2 can promote either Gαq-dependent activation or β-arrestin-dependent inhibition of PI3K, in a cell-type specific fashion. 3) PAR-2 evoked ERK1/2 activation is mediated through both G-protein and β-arrestin-dependent pathways-leading to distinct cellular outcomes. While G-protein-dependent ERK1/2 activation leads to proliferation, β-arrestin-dependent ERK1/2 activation leads to cell migration. These studies have major implications for PAR-2 as a therapeutic target. First, they point to the importance of evaluating both G-protein dependent and β-arrestin-dependent signaling when screening receptor agonists and antagonists. Second, they raise the possibility that pathway-specific agonists and antagonists could be developed. Third, they suggest that the outcome of PAR-2 activation may vary between tissues and cell types, depending on the expression patterns of β-arrestins, Gαq, or other components of each pathway.