Are energy demands too high, or our energy resources either too low or inappropriately prioritized, as we develop stress and/or depression? We review evidence of dysregulated cellular energy homeostasis and energy depletion in stress and depression, identifying factors that might limit energy substrate availability. Resetting of cellular energy-sensors, splanchnic hypoxia, and catecholamine effects on blood viscosity emerge as mechanisms that might disrupt normal energy homeostasis, accelerate cell injury, and cause depression-like symptoms in severe or prolonged stress. In particular, a vicious cycle of capillary dysfunction, cellular hypoxia, and inflammation emerges as a mechanism, by which prolonged stress might accelerate the development of diseases, including depression, in later life. Oxygen is a substrate for both serotonin- and ATP-synthesis, and the review therefore analyzes evidence of reduced oxygen availability in neurological diseases with high incidence of depression. Blood supply and oxygen availability are also keys to the inference of neuronal activity by functional neuroimaging. We review how neurotransmitters interfere with blood flow regulation, affecting interpretations of neuroimaging studies in stress and depression.