Fibromyalgia is a chronic, idiopathic condition of widespread musculoskeletal pain that is clinically characterized by muscle and soft tissue aches and tenderness, chronic fatigue, anxieties, sleep disturbances, as well as, cognitive dysfunction. Fibromyalgia is quite common in patients with systemic mast cell activation disease and is correlated with elevated serum levels of corticotropin-releasing hormone (CRH) and Substance-P leading to blood-brain-barrier disruption through brain mast cell activation and the selective release of mast cell mediators such as IL-6, TNF, histamine, bradykinin, IL-1, IL-6 and prostaglandin D2. Several studies have demonstrated that mast cells play a crucial role in mediating neuro-inflammation often triggered by immune system, environmental, infectious or stress triggers. Further, with the close functional and anatomical association of mast cells with sensory nerves in the skin, the increased amount of inflammatory mediators and neuro-sensitizing molecules likely contribute to increased tonic input into the central nervous system (in a study the number of mast cells were increased in the papillary dermis up to 14 times compared to controls in 100% of study participants). The higher prevalence of Fibromyalgia in women could possibly be explained by the fact that estradiol augments substance P-induced mast cell activation via stimulation of mast cell estrogen receptors. In summary, the increased amount of mast cell inflammatory mediators and triggered neuro-sensitizing molecules lead to chronic Fibromyalgia symptoms. In consequence, the controlled inhibition of mast cell activation and potentially required reduction of mast cell accumulation could lead to significant breakthrough in the treatment of Fibromyalgia which currently lacks satisfactory treatment options. Fibromyalgia is estimated to affect 2%–8% of the adult population and is considered to be the most common cause of generalized musculoskeletal pain in women between the ages of 20 and 55 years. Severe forms of fibromyalgia affects about 120 million people globally.