Neurologists and primary care practitioners treating patients with neurologic diseases are often called on to address complaints of fatigue. This symptom often limits patients’ independence and quality of life out of proportion to the degree of their neurologic impairment, and is a major cause of disability. Determining the cause and best treatment strategies for patients with this difficult symptom may be challenging. This review summarizes the mechanisms underlying central and peripheral fatigue, provides an overview of the nature of fatigue in common neurologic conditions, and discusses recent advances and recommendations in the treatment of fatigue affecting patients with neurologic disorders.