The present-day cardiac myocyte mitochondrion is much more complex than the basic machinery at the beginnings of chemiosmosis and oxidative phosphorylation. Indeed, it acts in constant and extensive symbiosis with its host cell sarcoplasm and with several organelles where information is transmitted back and forth to benefit the survival of the cell, its tissues, and the species. This includes not only mitochondrial biogenesis, fission and fusion, but also elimination of dysfunctional mitochondria and cells by apoptotic and necrotic pathways. Acute mitochondrial control is modulated by many factors including fast Ca2+ and K+ influx through mitochondrial channels, with slow Ca2+ and K+ efflux via mitochondrial exchangers, both of which modulate mitochondrial respiration, which in turn can modify the response to oxidant or ischemic stress. Mitochondrial Ca2+ levels can also modulate enzyme activity in the tricarboxylic acid cycle, but too much Ca2+ loading can stress the respiration machinery enough to fail with loss of the proton motive force. This can occur when the mitochondrial Ca2+ buffering capacity is exceeded. How this happens is inferred by experimental studies. Mild and temporary mitochondrial stress promotes the generation of hydrogen peroxide, which is linked to protection in isolated and in situ mitochondria against a subsequent, greater stress. Studies indicate that the opening of mitochondrial Ca2+-sensitive K+ channels during Ca2+ loading or mitochondrial stress induces the generation of superoxide radicals and hydrogen peroxide and causes mitochondrial swelling that is relieved by removal of the excess K+ in exchange for H+ influx. Evidence suggests this causes a proton leak (mitochondrial uncoupling) which stimulates respiration to enhance forward electron transfer to boost mitochondrial bioenergetic activity. In addition to mitochondrial protection against acute stress, mitochondria adapt to chronic changes (quality control) by induction of biogenesis, fission and fusion, and mitophagy. This results in a heterogeneity between normal and stressed or damaged mitochondria with differential expression of mitochondrial enzymes involved in bioenergetics, quality control, and regulation. The signals emitted by mitochondria induce nuclear and sarcoplasmic factors within the mitochondrial-associated membranes to target pathways that protect, propagate, and repair mitochondria, but also to trigger their demise and elimination.