Cardiopulmonary bypass is an integral and indispensable part of surgical repair of congenital heart defects. While the complications and morbidity secondary to the use of cardiopulmonary bypass has decreased considerably, there remains a significant incidence of clinically relevant renal and neurological injury. To provide more physiological delivery of oxygenated blood to the end-organs, our center has been successfully using a high-flow, high hematocrit cardiopulmonary bypass strategy since 2006. The essential components of this strategy include maintaining high flows (typically 200 mL/kg/min in neonates, 150–175 mL/kg/min in older infants weighing <10 kg, and 2.6 L/min/m2 in older children) throughout the duration of cardiopulmonary bypass irrespective of patient temperature, as well as maintaining a hematocrit of at least 32% on cardiopulmonary bypass. The incidence of post-operative acute kidney injury (around 3%) and clinical acute neurological events (<1%) with this strategy is considerably less when compared to other contemporary publications using the conventional cardiopulmonary bypass strategy. In this review, we discuss the rationale behind our approach and present evidence to support the high-flow, high-hematocrit strategy. We also discuss the practical aspects of our strategy and describe the adjuncts we use to derive additional benefits. These adjuncts include the use of a hybrid pH/alpha stat strategy during cooling/rewarming, aggressive use of conventional ultrafiltration during cardiopulmonary bypass, a terminal hematocrit of 40–45%, and avoidance of milrinone and albumin in the early peri-operative period. This results in a very low incidence of post-operative bleeding, facilitates chest closure in the operating room even in most neonates, helps in reducing the need for post-operative blood product transfusion and helps in achieving a favorable post-operative fluid balance early after surgery.