Energy is required to sustain life and enable stress adaptation. At the cellular level, energy is largely derived from mitochondria – unique multifunctional organelles with their own genome. Four main elements connect mitochondria to stress: 1) Energy is required at the molecular, (epi)genetic, cellular, organ, and systemic levels to sustain components of stress responses; 2) Glucocorticoids and other steroid hormones are produced and metabolized by mitochondria; 3) Reciprocally, mitochondria functionally respond to neuroendocrine and metabolic stress mediators; and 4) Experimentally manipulating mitochondrial functions alters physiological and behavioral responses to psychological stress. Thus, mitochondria are endocrine organelles that provide both the energy and signals that enable and direct stress adaptation. Neural networks regulating social behavior – as well as psychopathological processes – are also influenced by mitochondrial energetics. An integrative view of stress as an energy-driven process opens new opportunities to study mechanisms of adaptation and regulation across the lifespan.