Fatigue is a common and potentially debilitating symptom of neuromuscular disease (NMD). Studies show that patients with NMD subjectively report increased levels of fatigue. Laboratory testing has demonstrated that patients with NMD show objective physiological signs of increased fatigue, with both central and peripheral components. To date, no treatment has been proven to be truly effective through evidence-based medicine. Thus, the clinician must use a multimodality approach to treating fatigue in patients with NMD. Management interventions are generally based on a sequential approach including treatment of comorbid factors, with the goal of maximizing physical and psychological functioning. This might include low-intensity exercise training, cognitive therapy, treatment of associated depression, correction of risk factors such as obesity, poor nutrition, and inactivity (deconditioning). Optimizing cardiopulmonary function is also critical and measures such as noninvasive, positive pressure ventilation may reduce fatigue in patients with NMD. Novel medications such as modafinil, a nonamphetamine stimulant, may be a helpful pharmacological treatment. Nutraceutical agents, such as creatine monohydrate, coenzyme Q10 (CoQ10), and alpha-lipoic acid, may also improve neuromuscular function and reduce fatigue.