Patients who have major orthopaedic surgery are at high risk for developing venous thromboembolism (VTE). Assessment of risk and treatment to prevent VTE are considered standard of care due to its significant morbidity, potential mortality, and clinical burden and cost. Guidelines are available aiding orthopaedic surgeons to choose the best methods of VTE prophylaxis. Optimal VTE prevention has not been achieved. Recent advances in the understanding of the coagulation cascade have evolved because of a novel understanding of the molecular influences on the coagulation pathway. Subsequently, new anticoagulants have been developed that target specific factors within the coagulation cascade that are contrasted to the currently used agents that have a broad effect on the coagulation pathway. Multiple clinical trials have tested the new anticoagulants within the orthopaedic total knee and total hip arthroplasty arena. In addition, research to find new ways to prevent VTE was driven by limitations of the currently available agents. The new oral anticoagulants extensively trialed in orthopaedics are dabigatran, rivaroxaban, and apixaban. Clinical trials indicate that the new oral agents have the potential to impact VTE prophylaxis in regard to efficacy, predicta bility and consistency, clinical monitoring, adherence as to use and duration, and convenience. Concerns persist regarding issues of bleeding complications, liver enzyme elevation, patients with renal disease, and drug-to-drug interactions. The new oral agents do not have an antidote to reverse bleeding effect and have no reliable assay to measure effect. Nurses need to be aware of these new VTE prophylactic choices and their implications in order to provide the best outcomes for their patients.