Fatigue, best described as an overwhelming feeling of tiredness and exhaustion, occurs in the context of various neurological diseases. The high prevalence of fatigue as either a symptom or a comorbidity of neurological disease must be taken seriously, as fatigue interferes with patients' activities of daily living, has a remarkable negative impact on quality of life, and is a major reason for early retirement. The tremendous consequences of fatigue are consistent across neurological diseases, as is the uncertainty concerning its underlying pathophysiological mechanisms. Inconsistencies in defining fatigue contribute to the present situation, in which fatigue represents one of the least-studied and least-understood conditions. Tools for assessing fatigue abound, but few can be recommended for clinical or research use. To make matters worse, evidence-based pharmacological treatment options are scarce. However, non-pharmacological approaches are currently promising and likely to become of increasing importance. In sum, fatigue is challenging for both health-care professionals and patients. The present article aims to provide a comprehensive review of the literature on fatigue in neurological disease, and to reveal its complexity, as well as weaknesses in the concept of fatigue itself.