The different isoforms of profilin are known regulators of actin polymerization, and Joan Brugge and colleagues now show that profilin isoforms 1 and 2 have opposing functions in regulating cell migration and invasion. Unlike profilin 1, profilin 2 engages an ENA/VASP protein, EVL, and reduces membrane protrusion and cell migration through an actomyosin contractility mechanism. Downregulation of profilin 2 or EVL induces migration and invasion in cell lines, and reduced expression of these proteins correlates with invasive disease and a poor prognosis in patients with breast cancer.