Background: Unfractionated heparin (UFH) is the standard anticoagulant during cardiopulmonary bypass (CPB). A clinically relevant subset develops heparin resistance (HR)—failure to reach adequate anticoagulation with usual UFH—raising thrombotic risk and complicating perioperative care. Objectives: To synthesize contemporary evidence on the mechanisms, clinical implications, and perioperative management of HR in adult cardiac surgery with CPB. Methods: This narrative review synthesizes contemporary evidence on the epidemiology, mechanisms, recognition, and management of HR in adult cardiac surgery with CPB, emphasizing clinically actionable points. Results: Incidence varies across centers and definitions. Mechanisms include antithrombin (AT) deficiency or consumption and AT-independent drivers such as systemic inflammation or sepsis, protein-loss states, thrombocytosis, hyperfibrinogenemia, obesity, prior heparin exposure, and drug interactions. Sole reliance on activated clotting time (ACT) may misestimate anticoagulant effect; anti–factor Xa (anti-Xa) assays or heparin titration systems improve assessment when available. Management is stepwise: UFH dose escalation; targeted AT supplementation (or fresh frozen plasma where concentrates are unavailable); and transition to direct thrombin inhibitors when HR persists or UFH is contraindicated. Protocolized pathways and multidisciplinary coordination reduce delays and adverse events. Conclusions: HR is a multifactorial, common challenge in CPB. Pre-bypass risk assessment, multimodal monitoring, and an algorithm prioritizing UFH optimization, AT repletion, and timely use of direct thrombin inhibitors provide a pragmatic framework to limit thrombosis and bleeding. Harmonized definitions and comparative trials remain priorities.