The process of sprouting angiogenesis involves activating endothelial cells in a quiescent monolayer of an existing vessel to degrade and migrate into the underlying matrix to form new blood vessels. While the roles of biochemical factors in angiogenic sprouting have been well characterized, the roles of fluid forces have received much less attention. This review summarizes results that support a role for wall shear stress in post-capillary venules as a mechanical factor capable of synergizing with biochemical factors to stimulate pro-angiogenic signaling in endothelial cells and promote sprout formation.