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Cardiopulmonary bypass (CPB) has been used in veterinary medicine in experimental surgery and to address congenital and acquired diseases. We review the veterinary literature and expose common challenges of CPB in dogs and cats. Specifically, we describe the most specific elements of this technique in veterinary patients. The variety in animal size has made it difficult to standardize cannulation techniques, oxygenators, and priming volumes and solutions. The fact that one of the most common cardiovascular disorders, mitral valve disease, occurs predominantly in small dogs has limited the use of bypass in these patients because of the need for small, low prime oxygenators and pumps that have been unavailable until recently. Coagulation, hemostasis, and blood product availability have also represented important factors in the way CPB has developed over the years. The cost and the challenges in operating the bypass machine have represented substantial limitations in its broader use.