Mitochondria sense and respond to many stressors and can support either cell survival or death through energy production and signaling pathways. Mitochondrial responses depend on fusion-fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, including with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.