The aging process is accompanied by the onset of disease and a general decline in wellness. Insights into the aging process have revealed a number of cellular hallmarks of aging, among these epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Mitochondrial dysfunction increasingly appears to be a common factor connecting several of these hallmarks, driving the aging process and afflicting tissues throughout the body. Recent research has uncovered a much more complex involvement of mitochondria in the cell than has previously been appreciated and revealed novel ways in which mitochondrial defects feed into disease pathology. In this review we evaluate ways in which problems in mitochondria contribute to disease beyond the well-known mechanisms of oxidative stress and bioenergetic deficits, and we predict the direction that mitochondrial disease research will take in years to come.