Central sensitization, a pathophysiologic process in which the central nervous system undergoes changes that alter its processing of pain and other sensory stimuli, may be the mechanism underlying various conditions in which patients have unexplained pain and fatigue. Patients frequently misunderstand the cause of their symptoms and pursue unnecessary evaluations and treatments. Clinicians have a pivotal role in decreasing this misunderstanding by providing patient education, which can affect perception, management, functional status, and quality of life.