Lifestyle interventions are the first line of defense employed by many clinicians to both treat and prevent metabolic disorders associated with obesity, such as type 2 diabetes. Other clinical interventions, such as surgery, also are being rapidly implemented for these groups of patients. There is growing evidence that the benefit of these lifestyle and surgical treatments for patients might be driven by effects on mitochondrial function. This chapter will discuss the current knowledge about the influence of lifestyle and clinical interventions on mitochondrial health. The effects of lifestyle interventions such as dietary intervention, exercise, and physical training regimes, cessation of smoking, and cessation of alcohol will be discussed. Highly effective nonpharmacological clinical interventions, such as bariatric surgery and its effects on mitochondrial health, will also be reviewed.