Fatigue is a common symptom in primary care with many causes ranging from benign to life threatening. Appropriate evaluation and management are guided by the patient's history, which provides valuable clues as to the source of the patient's symptoms. Ultimately a diagnosis may not be identified for many patients presenting with fatigue, and in these patients management is the most challenging. This article offers guidance in the management of patients presenting with fatigue including key aspects of the patient's history of present illness, the building of a differential diagnosis, rational evaluation in a patient with a nondiagnostic history, and management in the setting of a nondiagnostic work-up.