Fatigue is among the top 10 reasons patients visit primary care offices, and it significantly affects patients' well-being and occupational safety. A comprehensive history and cardiopulmonary, neurologic, and skin examinations help guide the workup and diagnosis. Fatigue can be classified as physiologic, secondary, or chronic. Physiologic fatigue can be addressed by proper sleep hygiene, a healthy diet, and balancing energy expenditure. Secondary fatigue is improved by treating the underlying condition. Cognitive behavior therapy, exercise therapy, and acupuncture may help with some of the fatigue associated with chronic conditions. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, severe, and potentially debilitating disorder with demonstrated inflammatory, neurologic, immunologic, and metabolic abnormalities. ME/CFS has a poor prognosis, with no proven treatment or cure. It may become more common after the COVID-19 pandemic because many patients with long COVID (post-COVID-19 condition) have symptoms similar to ME/CFS. The most important symptom of ME/CFS is postexertional malaise. The 2015 National Academy of Medicine diagnostic criteria diagnose ME/CFS. Exercise can be harmful to patients with ME/CFS because it can trigger postexertional malaise. Patients should be educated about pacing their activity not to exceed their limited energy capacity. Treatment should prioritize comorbidities and symptoms based on severity.