Each year millions of patients experience a venous thromboembolic event. Due to the significant morbidity and mortality associated with venous thromboembolism (VTE), prevention is critical. Several groups, such as those undergoing orthopedic or general surgery, and patients experiencing acute myocardial infarction, are known to be at high risk for VTE. General medical patients-the medically ill-are also at risk, but they receive insufficient prophylaxis, which may be due to underestimation or lack of assessment of their risk. The American College of Chest Physicians recommends either unfractionated heparin or low-molecular-weight heparin to prevent VTE in these patients. The different pharmacologic profiles and dosing methods of these two groups of agents suggest that efficacy and safety may not be equivalent. Due to heterogeneity of medically ill patients and variability in clinical trials, a detailed review of the literature was performed to assist clinicians in assessing risk and choice of a regimen to prevent VTE.