Pulmonary embolism and deep vein thrombosis are serious complications of non-surgical patients, but scarcity of data documenting prophylaxis means antithrombotic therapy is rarely used. Prediction of risk is complicated by the variation in the medical conditions associated with venous thromboembolism (VTE), and lack of data defining risk in different groups. Accurate risk assessment is further confounded by inherited or acquired factors for VTE, additional risk due to medical interventions, and interactions between risk factors. Acquired and inherited risk factors may underlie thromboembolic complications in a range of conditions, including pregnancy, ischaemic stroke, myocardial infarction and cancer. Risk stratification may be feasible in non-surgical patients by considering individual risk factors and their cumulative effects. Current risk assessment models require expansion and modification to reflect emerging evidence in the non-surgical field. A large on-going study of prophylaxis with low-molecular-weight heparin in non-surgical patients will clarify our understanding of the components of risk, and assist in developing therapy recommendations.