Angiotensin II (Ang II) has been reported to induce migration in neuronal cell types. Using time-lapse microscopy, we show herein that Ang II induces acceleration in NG108–15 cell migration. This effect was antagonized by PD123319, a selective AT₂ receptor antagonist, but not by DUP753, a selective AT₁ receptor antagonist, and was mimicked by the specific AT₂ receptor agonist CGP42112. This Ang II-induced acceleration was not sensitive to the inhibition of previously described signaling pathways of the AT₂ receptor, guanylyl cyclase/cGMP or p42/p44^mapk cascades, but was abolished by pertussis toxin treatment and involved PP2A activation. Immunofluorescence studies indicate that Ang II or CGP42112 decreased the amount of F-actin at the leading edge of the cells. This decrease was accompanied by a concomitant increase in G-actin levels. Regulation of actin turnover in actin-based motile systems is known to be mainly under the control of the actin depolymerizing factor (ADF) and cofilin. Basal migration speed decreased by 77.2% in cofilin-1 siRNA-transfected NG108–15 cells, along with suppression of the effect of Ang II. In addition, the Ang II-induced increase in cell velocity was abrogated in serum-free medium as well as by genistein or okadaic acid treatment in a serum-containing medium. Such results indicate that the AT₂ receptor increases the migration speed of NG108–15 cells and involves a tyrosine kinase activity, followed by phosphatase activation, which may be of the PP2A type. The present study hence identifies actin depolymerization and cofilin as new targets of AT₂ receptor action, in the context of cellular migration.