The prevailing view of the behavior of the smooth muscle wall of large arteries is described by the Windkessel hypothesis, in which the wall does not actively contract in synchrony with the cardiac cycle. This hypothesis has predominated for well over a century. By contrast, several lines of evidence show that the smooth muscle wall of the aorta and other large arteries is capable of undergoing contractions at the rate of the heartbeat and that these contractions are neutrally-mediated (i.e., pulse synchronized contractions [PSCs]). The pacemaker for PSCs resides in the right atrium, and direct electrical stimulation of the aorta results in similar contractile activity. PSCs represent a modified platform to understand the etiology of cardiovascular diseases and may allow for the development of new therapeutic targets.