Venous thromboembolism (VTE), encompassing pulmonary embolism (PE) and deep venous thrombosis (DVT), is a major cause of morbidity and mortality of particular relevance for intensivists and hospitalists. Acute VTE is usually managed with parenteral unfractionated heparin or low-molecular-weight heparin, followed by an oral vitamin K antagonist. Data are lacking for optimal treatment of less common occurrences, such as upper extremity DVT, and for approaches such as thrombolysis for PE associated with early signs of hemodynamic compromise or inferior vena cava filters when anticoagulation is contraindicated. Direct oral anticoagulants (DOACs) including apixaban, dabigatran, edoxaban, and rivaroxaban are now added to the armamentarium of agents available for acute management of VTE and/or reducing the risk of recurrence. This review outlines an algorithmic approach to acute VTE treatment: from aggressive therapies when anticoagulation may be inadequate, to alternative choices when anticoagulation is contraindicated, to anticoagulant options in the majority of patients in whom anticoagulation is appropriate. Evidence-based guidelines and the most recent DOAC clinical trial data are discussed in the context of the standard of care. Situations and treatment approaches for which data are unavailable or insufficient are identified. VTE therapy in care transitions is discussed, as are choices for secondary prevention.