Although up to 80% of fatal pulmonary emboli occur in nonsurgical patients, conclusive studies on the prevention of thrombosis have only become available in the last 10 years. Bedridden inpatients with acute medical diseases require pharmacologic prophylaxis for thrombosis with unfractionated or low molecular weight heparin or with fondaparinux. This also holds true for patients with underlying malignancies or those suffering from acute ischemic stroke or paretic leg. The challenges to thrombosis prophylaxis are posed by ensuring that uninterrupted prophylaxis is continued after hospital discharge in cases of persisting risk, determining the indications and applying thrombosis prophylaxis on an outpatient basis as well as the multimorbidity and often advanced age of the internal medicine patients. The last factor not only entails an elevated risk of thromboembolism but also an increased risk of hemorrhage, especially in patients with renal insufficiency or platelet inhibitors. Product-specific recommendations and restrictions on pharmacologic prophylaxis need to be considered. Thromboprophylaxis as applied in internal medicine and family practice represents an effective measure to prevent symptomatic and fatal thromboembolisms, but due to multimorbidity and polytherapy of medical patients it requires careful monitoring.