A critical aspect of cardiopulmonary bypass (CPB) is achieving full anticoagulation to prevent thrombosis and consumptive coagulation (CCA). Systemic anticoagulation with heparin during CPB should be completely neutralized by administering protamine to restore normal hemostasis. Activated clotting time (ACT) is a major marker of anticoagulation management during CPB. However, studies have shown that ACT measurements can vary predictably with different point-of-care testing ACT devices, suggesting the importance of considering the ACT device when determining the target ACT. Otherwise, the amount of heparin used and circulating during CPB can be unnecessarily high. Calculating an optimal protamine dose (PD) is challenging. Yet, newer strategies and heparin concentration-based dosing indicate that average doses of 60–90 mg/m² are generally sufficient. This equates to a protamine-to-heparin ratio of approximately 0.5–0.8:1 of the first heparin bolus to establish the target ACT before going on CPB or a 0.3–0.5:1 of the total heparin dose during CPB. PD exceeding 90 mg/m² may result in residual free protamine. Excessive use of heparin and protamine has been associated with increased post-operative bleeding. This review discusses several considerations in planning an anticoagulation strategy during CPB, focusing on the predictable differences of ACT devices and strategies to determine the optimal PD. The aim is to administer a safe and minimal amount of heparin to protect the CPB circuit and patient from thrombosis and CCA, and to administer the optimal amount of protamine to completely neutralize the circulating heparin without leaving residual free protamine.