The majority of fatal cases of pulmonary embolism in hospitalized patients occur in acutely ill, medically treated patients. Current guidelines, based on a large number of prospective, randomized, controlled trials evaluating the safety and efficacy of pharmacologic venous thromboembolism (VTE) prophylaxis in medical patients, now recommend using VTE prophylaxis in this population. Unfortunately, prophylaxis rates in medical patients are unacceptably low, despite efforts to develop strategies for improving implementation of prophylaxis regimens. Studies indicate that a substantial proportion of patients with VTE present after hospital discharge, but no clinical trials evaluating VTE prophylaxis for medical outpatients have yet been published. In this Review, we examine the literature on VTE prophylaxis in hospitalized medical patients, and evaluate the available data for the outpatient setting.