Most strokes are caused by the mechanisms already described, i.e., cardioembolism, atherosclerosis, and small-vessel disease, but at least 20% are due to other mechanisms. This is even more likely in younger patients (< 40 years old), and in older patients without atherosclerotic risk factors. The following is our approach to stroke diagnosis in younger patients and older patients in whom the cause remains obscure after the usual evaluation of the heart for sources of emboli and cerebral vessels for atherosclerosis, or who continue to have strokes despite standard treatment with antithrombotic agents and control of risk factors.