Methods to study exercise are evolving from classically integrative organ approaches towards the more fundamental cellular reactions. While in vitro cellular and molecular methods are well established, only recently has in vivo molecular manipulation been widely used. This review discusses two complementary methods for determining in vivo the significance of one gene thought important to exercise: vascular endothelial growth factor (VEGF). Because VEGF deletion is embryonically lethal, its study requires conditional and/or organ-targeted strategies. We inactivated the muscle VEGF gene in two ways: