Fibromyalgia, chronic fatigue syndrome, and related illnesses fall under the spectrum of chronic multisymptom illnesses (CMI). This constellation of syndromes often is defined by chronic pain, unremitting fatigue, cognitive difficulties, and various other symptoms. In treating these illnesses, pharmacotherapy generally is the mode of choice, with exercise being overlooked often. However, research has shown that exercise is quite beneficial in reducing pain and fatigue in this population and should be included as part of a multimodal therapy regimen. This article reviews the exercise and CMI literature and provides a model for applying these evidence-based guidelines to a clinical population.