Background: A symptom cluster consisting of 'medically-unexplained' chronic fatigue, effort intolerance and widespread pain is a complex and still poorly understood condition. Purpose: To demonstrate the theoretical and clinical value of a biopsychosocially-oriented 'stress-adaptation' model for this multi-symptom illness. Methods: Clinical observation and review of the relevant literature. Results: Symptoms and functional limitations of these patients may reflect a loss of normal physical, mental and emotional adaptability, primarily based on stress system dysregulation. Conclusions: The proposed stress-adaptation model may facilitate diagnosis, defy dualistic causal thinking, and offer tailor-made treatment options to help patients find a better balance in their lives