Background Previous studies showed that exercise in cancer patients is feasible and may reduce fatigue and improve physical fitness and quality of life. However, many previous studies had methodological weaknesses related to trial design, sample size, comparison group, outcome measures, short follow-up durations and programme content. Purpose This paper aims to present the rationale and design of the clinical research subprogramme of the Alpe d'HuZes Cancer Rehabilitation (A-CaRe) programme. Method A-CaRe Clinical Research includes four randomized controlled trials in patients: (a) after chemotherapy, (b) during chemotherapy, (c) after stem cell transplantation and (d) during childhood cancer. These trials compare high-intensity resistance and endurance exercise interventions with usual care or a waiting list control group. In two studies, a second intervention arm consisting of low-to-moderate intensity exercise is included. All four A-CaRe trials use similar methods. Results Outcome measures are carefully chosen based on the International Classification of Functioning Disability and Health model. Measurements will be performed prior to randomization (T0), after completion of the intervention (T1) and at follow-up (T2). The primary outcome measures are cardiorespiratory fitness, muscle strength and fatigue. Secondary outcome measures include health-related quality of life and psychosocial functioning. Furthermore, costeffectiveness and cost-utility analyses are performed from a societal perspective. Conclusion We hypothesize that exercise is more effective at improving physical fitness and thereby reducing fatigue and more cost-effective compared with usual care or a waiting list control group. If so, the programmes will be implemented in the Dutch clinical practice. © International Society of Behavioral Medicine 2011.