A 46-year-old woman with a remote history of classical migraine had development of pain behind her left eye followed by holocephalic headache. She subsequently began to have episodic headaches. Her sleep became disrupted. Irritability, cognitive symptoms, and fatigue then developed. Her headaches occurred daily, along with whole-body discomfort. She underwent polysomnography and was diagnosed with obstructive sleep apnea syndrome. Her sleep quality improved with continuous positive airway pressure therapy, but her daily headaches, cognitive symptoms, and limb pain persisted. She was diagnosed with “seronegative Lyme disease.” Fourteen days of doxycycline therapy was not accompanied by improvement in symptoms. After extensive laboratory evaluations and consultations, the patient was diagnosed with fibromyalgia. Short trials of low doses of amitriptyline, nortriptyline, gabapentin, and pregabalin were undertaken, but these were poorly tolerated and discontinued in each instance. The patient was concerned that she may have multiple sclerosis, and she underwent magnetic resonance imaging of the brain. The radiology report documented multiple, small areas of T2-signal change, and demyelinating disease was included in the radiologic differential diagnosis. The patient then sought a second opinion. Evaluations at Mayo Clinic supported evidence of diffuse myofascial limb and back pain and tenderness. Brain magnetic resonance images were reviewed. Extensive work-up for alternative differential diagnostic considerations for her pain was unremarkable. The patient was diagnosed with fibromyalgia with features of central sensitization, with brain magnetic resonance imaging demonstrating nonspecific radiologic abnormalities. A detailed discussion about fibromyalgia and central sensitization was undertaken with the patient. The concepts rehabilitative approaches were reviewed. Slowly progressive, incremental, physical reconditioning, and cognitive behavioral retraining were recommended. She was advised to complete a fibromyalgia and chronic fatigue treatment program, focusing on cognitive and behavioral approaches, stress management, sleep hygiene, balanced lifestyle, moderation, energy conservation, and graded exercise. No new medications were recommended given her previous poor tolerance. The patient’s atypical symptoms, normal examination findings, and brain magnetic resonance imaging appearance assisted in excluding a diagnosis of demyelinating disease. The radiologic findings, termed white matter leukoaraiotic change, are commonly encountered in healthy persons as they age, particularly in patients with migraine or those with microvascular risk factors.