Mitochondria are undergoing a renaissance. The cellular power plant is now recognized as a key cellular signaling platform. The signals released by mitochondria are currently an area of intense research. A complex network is emerging involving metabolic intermediates, the roles of the mitochondrial unfolded protein response, and the interaction of mitochondria with other organelles and with the cellular autophagic system. Despite the diversity of the perturbations leading to mitochondrial diseases, some emerging trends are apparent. The long-held notion that mitochondrial diseases result from decreased mitochondrial energy output has been challenged by new data showing that mitochondrial pathological signaling can cause disease irrespective of the energy output. This review proposes a novel integrative view of mitochondrial signaling in physiology and disease.