In medical school, students learn about the human body by organ system. They spend a few weeks on the heart, then the lung, followed by the gastrointestinal tract. Eventually the whole body is covered. One of the fascinating developments in the last decade has been the functional linkage and new connections of seemingly diverse body systems. Fibromyalgia research finally hit its stride when important studies connected the nervous system, the endocrine (hormone) system, and the immune system. This enabled physicians to devise improved strategies to help fibromyalgia patients. Basic background information provided in this chapter will be expanded upon in later parts of the book when we review treatments. Within the brain is a small region known as the hypothalamus. It makes releasing hormones that travel down a short path to the pituitary gland, which makes stimulating hormones. The stimulating hormones send signals to tissues where hormones are manufactured for specialized functions. Table 3 and Figure 9 show how thyroid, cortisol, insulin, breast milk, and growth hormone are made along the hypothalamic-pituitary axis and the hypothalamic-pituitary-adrenal (HPA) axis. We have already mentioned that emotional stress can bring on or aggravate fibromyalgia. At the National Institutes of Health and the University of Michigan, studies have firmly established some of the factors important in this relationship. The role of corticotropin-releasing hormone (CRH), the precursor or ancestor of the steroid known as cortisol, has been the focus of much of this work. Even though CRH levels are normal in fibromyalgia, CRH responses (stress responses) to different forms of stimulation are blunted. CRH has many important interactions other than leading to the production of steroids. Its expression can be increased by stress, serotonin, and estrogen. Endorphins promote the secretion of CRH. Decreased sympathetic nervous system activity in the adrenal glands and substance P, as well as nitric oxide, can turn off CRH production. Rats with abnormally low stress responses develop many of the features we associate with fibromyalgia. How do these interrelationships translate into a fibromyalgia patient’s feeling of being unwell? The answer is not clear. However, these studies suggest that fibromyalgia patients do not respond normally to acute stress and do not release enough adrenalin.