This article considers how regulation of signaling controlled by cytosolic NADPH and NADH redox systems contained within the vascular smooth muscle cell may contribute to coordinating alterations in force generation elicited by acute changes in oxygen tension. Additional important issues considered include defining when oxidases generating reactive oxygen species (ROS), such as Nox oxidases, or ROS metabolizing activities which utilize cytosolic NADH and/or NADPH are key participants in eliciting responses that are observed, and assessing how mitochondria can potentially contribute to the regulation that is seen. Many important signaling mechanisms potentially involved in vascular oxygen sensing such as potassium channels, systems regulating intracellular calcium, and the sensitivity of the contractile apparatus to calcium, and the control of cGMP-mediated relaxation by soluble guanylate cyclase appear to be regulated by cytosolic NAD(P)H redox and or ROS. Differences in the processes controlling the maintenance of cytosolic NADPH redox by the pentose phosphate pathway of glucose metabolism are hypothesized to be a key factor in controlling the expression of a relaxation to hypoxia seen in systemic arteries compared to the hypoxic contractile response observed in pulmonary arterial smooth muscle.