Warfarin has a very narrow therapeutic window and obvious interindividual variability in its effects, with many factors contributing to the body's response. Algorithms incorporating multiple genetic, environment and clinical factors have been established to select a precision dose for each patient. A number of randomized controlled trials (RCTs) were conducted to explore whether patients could benefit from these algorithms; however, the results were inconsistent. Some questions remain to be resolved. Recently, new genetic and non-genetic factors have been discovered to contribute to variability in optimal warfarin doses. The results of further RCTs have been unveiled, and guidelines for pharmacogenetically guided warfarin dosing have been updated. Based on these most recent advancements, we summarize some open questions in this field and try to propose possible strategies to resolve them.