BACKGROUND Adolescents with cancer experience distressing physical and psychosocial symptoms, especially during treatment. Fatigue and sleep disturbances commonly affect adolescents' quality of life, but little is known about how adolescents experience these symptoms during an early month of chemotherapy. This study measured fatigue, sleep disturbances, and quality of life in 20 adolescents over 1 month while they were receiving chemotherapy. METHODS Multidimensional fatigue and quality of life were measured weekly with modules from the PedsQL Measurement Model, and sleep disturbances were measured with the General Sleep Disturbance Scale. RESULTS Adolescents experienced increased severity of fatigue and sleep disturbances during the week after treatment. Common sleep-wake problems included daytime sleepiness, decreased alertness, and poor sleep quality. Fatigue and sleep-wake disturbances were related symptoms, and both symptoms were associated with various domains of quality of life. CONCLUSIONS Fatigue and sleep-wake disturbances are significant problems for adolescents receiving chemotherapy and negatively affect the quality of life. Clinicians should routinely screen adolescent patients for fatigue and sleep disturbances and intervene to minimize their impact using pharmacologic and nonpharmacologic strategies.