Venous thromboembolism includes deep vein thrombosis and pulmonary embolism and is a serious medical condition that requires anticoagulation as part of treatment. Currently, standard therapy consists of parenteral anticoagulation followed by a vitamin K antagonist (VKA). The pharmacokinetic and pharmacodynamic profiles of the direct oral anticoagulants (DOACs) differ from VKAs, which overcome some of the limitations of VKAs and have practical implications on their use in clinical situations. Dabigatran is a prodrug that undergoes primarily renal elimination and does not affect cytochrome P450 enzymes. Assays to quantify the degree of anticoagulation and the therapeutic level of DOAC are either unavailable for routine clinical use or require specific calibration. Routine monitoring of DOACs is not recommended at this time. Dabigatran, rivaroxaban, and apixaban are DOACs that have been studied for treatment of venous thromboembolism. Clinical trials comparing DOACs with standard therapy have shown them to be non-inferior for acute and extended therapy. Each DOAC has a unique benefit and harm profile that should be considered prior to use. The distinguishing characteristics of dabigatran include a requirement of parenteral anticoagulation prior to acute treatment, clinical trial results comparing it with a VKA for extended treatment, association with upper gastrointestinal adverse events, and increased risk of gastrointestinal bleed. Rivaroxaban is the only DOAC that has once-daily dosing while apixaban is the only DOAC that has lower risk of overall, major, and gastrointestinal bleeding compared with VKA. A common drawback of DOACs is the lack of an available reversal agent. Clinical trials of reversal agents are ongoing and one application for approval has been submitted to the US Food and Drug Administration. Selection of a DOAC for acute and extended therapy requires a shared decision-making approach that includes a comprehensive assessment of the benefits and harms of each individual DOAC.