Research of patients with defects in cellular energy metabolism (mitochondrial disease) has led to a better understanding of mitochondrial biology in health and disease. The obtained knowledge is of increasing importance for physicians of all medical disciplines. It assists in enabling the development of rational treatment strategies for diseases or conditions caused by mitochondrial dysfunction. The still frequently used classical interventions with vitamins or co-factors are only beneficial in some rare mitochondrial disease conditions, like coenzyme Q biosynthesis defects. For that reason alternative strategies to correct disturbed energy metabolism have to be developed. New approaches in this direction include nutrition and exercise therapies, alternative gene expression, enzyme-replacement, scavenging of potentially toxic compounds and modulating cell signalling. The effect of some of these interventions has already been explored in humans whilst others are still at the level of single cell research. We review the state of the art of the development of mitochondrial treatment strategies and discuss what steps need to be taken to efficiently approach the huge burden of disease caused by dysfunctional mitochondria.