Purpose: Delivery of exercise interventions to patients with early-stage breast cancer undergoing chemotherapy requires complex clinical decisions. The purpose of this study was to develop a framework to support clinical decisions for tailoring exercise interventions to common comorbidities and cancer treatment-induced adverse effects. Method: Tailored exercise prescriptions were developed in four steps, following the i3-S strategy. All steps were based on current best available evidence, complemented with expert opinions. First, common comorbidities and treatment-induced adverse effects were identified. In the subsequent steps, contra-indications and restrictions for exercise were described, along with possible exercise adaptations. In the final step, the obtained information was synthesized into a framework. Results: Prevalent comorbidities were hypertension, heart disease, diabetes mellitus, (osteo)arthritis, chronic obstructive pulmonary disease, and obesity. Adverse effects included conditions induced by pretreatment (e.g., lymphedema as a result of surgery) or by chemotherapy (e.g., reduced blood cell counts). Adaptations to the recommended exercise program were related to exercise tolerance, safety, and hygiene. A framework was proposed to guide clinical decisions during the exercise intervention. Conclusion: Comorbidities and adverse effects of breast cancer treatment require exercise adaptations. The proposed framework provides guidance on tailored exercise prescriptions in patients with breast cancer undergoing chemotherapy.Implications for RehabilitationExercise is recommended for patients with breast cancer undergoing chemotherapy, but requires complex clinical decisions of the health professional.We identified the most important comorbidities and adverse effects of breast cancer treatment, and the resultant contra-indications and restrictions to exercise.We incorporated these findings into a clinical decision framework that provides suggestions for exercise adaptations in patients with breast cancer undergoing chemotherapy.