From a biopsychosocial perspective, individuals with chronic fatigue syndrome face a variety of quality-of-life challenges, including fluctuating physical symptomatology, neurocognitive impairment, loss of social support, and, for many, psychological distress that complicates the disability. The following case response describes a multidimensional assessment and treatment approach that emphasizes an empathic, empowering, and interactive clienttherapist relationship. The proposed assessment plan includes a semi-structured psychiatric interview; a measure of cognitive schema and coping; an in vivo measure of physical activity (actigraphy); self-ratings of fatigue severity, emotional functioning, and perceived energy; and measures of health care practices, sleep disorders, psychosocial functioning, and socioeconomic resources. The proposed treatment plan describes an individualized approach to cognitive behavior therapy that includes self-monitoring and facilitating awareness of the interactive relationship among perceived and expended energy, fatigue severity, positive and negative emotion, and fatigue-exacerbating beliefs and behaviors.