Warfarin, the only available oral coumarin anticoagulant in South Africa, is widely prescribed for the prevention and management of arterial and venous thrombo-embolism. It has a narrow therapeutic index and a wide inter-individual variability in therapeutic response. Genetic polymorphism of the VKORC1 and CYP2C9 genes, as well as clinical factors such as age, gender, body mass index and interacting drugs explain less than 55% of variability in warfarin dose requirements. True warfarin resistance is rare (< 0.1%) and is defined as warfarin requirements greater than 70 mg per week to maintain the international normalised ratio (INR) in the target therapeutic range. As hereditary warfarin resistance is rare, non-adherence, laboratory errors and interactions should be excluded in patients with persistent sub-therapeutic INR levels. Pharmacogenetic models to estimate individualised warfarin doses do not take into account the mutations associated with warfarin resistance. In patients with presumed warfarin resistance, higher doses that maintain the INR in the target therapeutic range should be given, and the INR closely and regularly monitored.