Mature coronary collaterals, which develop during chronic coronary occlusion, are not simply passive conduits but are capable of active vasomotion. Collateral perfusion must traverse not only these vessels but also proximal and distal coronary vessels. This series of resistances significantly modulates perfusion to collateral-dependent and potentially ischemic myocardium. The collateral vessels themselves possess unique vasomotor characteristics, particularly markedly augmented constriction to vasopressin. The recipient coronary microcirculation develops endothelial dysfunction during collateral development, a phenomenon that may markedly alter neurohumoral regulation of perfusion to collateral-dependent myocardium. Finally, the resistances proximal to the origin of the collateral vasculature, which are negligible at rest, become significant when flow to nonischemic regions (non-collateral-dependent) is increased, predisposing to the collateral steal phenomenon. Although collateral vessels play a crucial role in preventing myocardial infarction and often restore both resting and exercise perfusion to normal, the need to use these vessels is associated with important alterations of regulatory mechanisms in the coronary circulation.