The choice of cannulation technique for cardiopulmonary bypass remains a critical decision in cardiac surgery with direct consequences for intraoperative management and patient outcomes. Central and femoral cannulation represent the 2 dominant approaches, each associated with unique anatomical considerations, hemodynamic implications, and perioperative risks. The correct selection of a cannulation strategy should limit the risk of embolic events and associated complications such as vascular injury and stroke. The purpose of this review is to provide a detailed comparison of central and femoral cannulation techniques, with an emphasis on clinical scenarios and outcomes, recent innovations, and state-of-the-art technology. By critically analyzing current evidence, we aim to offer insights into the optimal cannulation strategy tailored to specific patients.