In populations with serious medical illness, fatigue is highly prevalent and can have a major and adverse effect on quality of life. There is growing recognition among clinicians of the need to assess and manage fatigue at all stages of disease. Studies are needed to clarify the mechanisms that underlie various types of fatigue, understand the complex epidemiology of the symptom, and provide an evidence base for management decisions. To date, little research of this type has been performed. Fortunately, the past decade has witnessed substantial advances in fatigue assessment methodologies, and there are now extraordinary opportunities to advance fatigue-related research and provide new tools to benefit the quality of life of medically ill patients.