Purpose/Objectives: To examine the relationship between physical performance and fatigue in child and adolescent cohorts during the first three cycles of chemotherapy. Design: Prospective, observational design. Setting: Two pediatric cancer centers in the upper Midwest region of the United States. Sample: 16 children and 14 adolescents newly diagnosed with cancer. Methods: Standardized instruments were administered during the first and third cycles of chemotherapy. Instruments included physical performance tests (Timed Up and Down Stairs [TUDS] and the 6-Minute Walk Test [6MWT]) and a self-report fatigue scale. Main Research Variables: Fatigue and physical performance. Findings: In the child cohort, physical performance appeared to improve and fatigue diminished from cycle 1 to 3 of chemotherapy. When time on TUDS decreased, fatigue tended to decrease; when 6MWT distance increased, fatigue decreased. In the adolescent cohort, fatigue seemed to decrease but physical performance measures evidenced little change. Correlations between changes in the physical performance variables and fatigue were not significant. Conclusions: Fatigue may decrease early in treatment as disease symptoms resolve. Fatigue in the child cohort was related to physical performance, which is consistent with previous studies that defined fatigue in children as primarily a physical sensation. Findings in the adolescent cohort support research that defined adolescent fatigue as more complex with mental, emotional, and physical components. Implications for Nursing: Knowing how fatigue relates to physical performance in children and adolescents informs the nurse in educating patients and families about symptom management.