Anticoagulants are widely used in medical and surgical settings, with increasing costs and prescriptions for direct oral anticoagulants (DOACs). Warfarin remains widely prescribed, but DOACs are increasingly used. Heparin-based anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs). Anticoagulants are generally well tolerated, but interindividual variability in response can lead to serious complications like thrombosis, haemorrhage, and heparin-induced thrombocytopenia (HIT). This review highlights genetic, environmental, and clinical factors influencing anticoagulant response and discusses current evidence for tailoring drug, dose, and monitoring decisions to improve safety. Validated variants in VKORC1, CYP2C9, and CYP4F2 are biomarkers for warfarin response, with genotype-informed dosing reducing adverse events. Polymorphisms in CES1 are relevant to dabigatran exposure, but genetic studies on bleeding are sparse. Body weight and anti-Xa levels merit further attention. Safe and effective anticoagulation requires deeper understanding of response variability and further research. Warfarin inhibits vitamin K 2,3 epoxide reductase complex 1 (VKORC1), reducing clotting factors and leading to anticoagulation. Warfarin has a narrow therapeutic window and large interindividual variability. Warfarin is monitored via INR, with a recommended range of 2.0–3.0. Warfarin response is influenced by age, ethnicity, weight, medications, diet, illness, and smoking. Genetic factors like CYP2C9 and VKORC1 variants affect warfarin dose requirements and bleeding risk. CYP2C9*2 and *3 reduce S-warfarin metabolism, while VKORC1 variants affect dose requirements and bleeding risk. CYP4F2 variants are associated with increased warfarin dose requirements. DOACs are alternatives to warfarin, with rapid onset, wider therapeutic windows, and fewer food and drug interactions. DOACs are prescribed at fixed doses without monitoring, but clinical and genetic factors can affect efficacy and safety. DOACs are effective for non-valvular AF and VTE, but warfarin remains the drug of choice for patients with mechanical heart valves. Factors affecting DOAC efficacy and safety include food and drug interactions, P-gp inhibitors, CYP450 inducers and inhibitors, and concomitant use of antiplatelets and NSAIDs. Weight and renal impairment affect DOAC pharmacokinetics, with dose adjustments recommended for obese and renal-impaired patients. Heparin resistance refers to the need for high heparin doses to achieve a therapeutic aPTT, with factors like AT deficiency and platelet count contributing. Heparin-inducedAnticoagulants are widely used in medical and surgical settings, with increasing costs and prescriptions for direct oral anticoagulants (DOACs). Warfarin remains widely prescribed, but DOACs are increasingly used. Heparin-based anticoagulants include unfractionated heparin (UFH) and low molecular weight heparins (LMWHs). Anticoagulants are generally well tolerated, but interindividual variability in response can lead to serious complications like thrombosis, haemorrhage, and heparin-induced thrombocytopenia (HIT). This review highlights genetic, environmental, and clinical factors influencing anticoagulant response and discusses current evidence for tailoring drug, dose, and monitoring decisions to improve safety. Validated variants in VKORC1, CYP2C9, and CYP4F2 are biomarkers for warfarin response, with genotype-informed dosing reducing adverse events. Polymorphisms in CES1 are relevant to dabigatran exposure, but genetic studies on bleeding are sparse. Body weight and anti-Xa levels merit further attention. Safe and effective anticoagulation requires deeper understanding of response variability and further research. Warfarin inhibits vitamin K 2,3 epoxide reductase complex 1 (VKORC1), reducing clotting factors and leading to anticoagulation. Warfarin has a narrow therapeutic window and large interindividual variability. Warfarin is monitored via INR, with a recommended range of 2.0–3.0. Warfarin response is influenced by age, ethnicity, weight, medications, diet, illness, and smoking. Genetic factors like CYP2C9 and VKORC1 variants affect warfarin dose requirements and bleeding risk. CYP2C9*2 and *3 reduce S-warfarin metabolism, while VKORC1 variants affect dose requirements and bleeding risk. CYP4F2 variants are associated with increased warfarin dose requirements. DOACs are alternatives to warfarin, with rapid onset, wider therapeutic windows, and fewer food and drug interactions. DOACs are prescribed at fixed doses without monitoring, but clinical and genetic factors can affect efficacy and safety. DOACs are effective for non-valvular AF and VTE, but warfarin remains the drug of choice for patients with mechanical heart valves. Factors affecting DOAC efficacy and safety include food and drug interactions, P-gp inhibitors, CYP450 inducers and inhibitors, and concomitant use of antiplatelets and NSAIDs. Weight and renal impairment affect DOAC pharmacokinetics, with dose adjustments recommended for obese and renal-impaired patients. Heparin resistance refers to the need for high heparin doses to achieve a therapeutic aPTT, with factors like AT deficiency and platelet count contributing. Heparin-induced