Increasing numbers of patients complaining of fatigue are presenting with complex symptoms that are not easily classifiable into specific ICD-9 diagnostic categories. In addition to problems with specific diagnoses, these patients are often refractory to treatment; yet continue to be plagued by fatigue, myalgias, cognitive impairment, depression and the like. Multiple physiological systems appear to be compromised including the adrenal glands, thyroid regulation, hepatic detoxification and even mitochondrial oxidative stress, creating a feed-forward cycle of inflammation, cellular dysfunction, and systemic dysregulation can often elicit novel treatment options in the care of these chronically unwell patients.