Mitochondria are responsible for energy production in unicellular and multicellular eukaryotes. Apart from their major role in metabolism, mitochondria are involved in many other cellular processes. A new paradigm is needed to understand aging, aging-related illnesses, and complex diseases. Because of the long co-evolution of mitochondria with the cells, subtle variations in the function of these organelles could influence many organ systems. Understanding the extent of this influence will shed light on the pathophysiology of some of these diseases. This review will examine the history of mitochondrial DNA research, and explain the role mitochondrial DNA plays in relation to complex diseases and their outcomes, like metabolic diseases, cancer and obesity. Finally, we will explore some of the new paradigms used in this research.