Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a debilitating disorder that affects about 60 million people worldwide and manifests commonly in the aftermath of a viral infection. Symptoms affect immune function, sleep patterns, and cognition and leave patients severely fatigued after normal or less than normal exertion. Mitochondria are responsible for energy metabolism, cell signaling, and oxidative stress pathways in majority of the tissues in the body. Presented here is a review of studies investigating the role of mitochondrial DNA mutations and oxidative phosphorylation output in immune cells and skeletal muscle cells. Also included are studies that are broad metabolomic investigations of blood plasma of ME/CFS patients, and studies that measure markers of oxidative stress. Immune dysfunction emerges to be playing a key role in ME/CFS pathophysiology as well as oxidative stress. Ultimately the interdependence of these processes with the mitochondria at the center starts to paint a clearer picture of the mechanisms at play in this disease.