The National Academy of Sciences has estimated that up to 2.5 million Americans suffer from Systemic Exertion Intolerance Disease also known as Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. While many physicians still believe this pathophysiological state is psychosomatic, there is a substantial evidence-base to show that these patients have neurological, immunological and autonomic variations out of the norm. We will examine the physiology of SEID/ME/CFS and look at the use of botanicals and nutraceuticals for the potential treatment of SEID/ME/CFS.