Patients with ischemic stroke of unclear etiology are often screened for hypercoagulable syndromes or thrombophilias. These have been recognized to cause venous thrombosis, and include hereditary deficiencies of coagulation factors, genetic mutations, or acquired disorders. However, the majority of coagulation disorders are only rarely associated with ischemic stroke. The tests most commonly used to screen for thrombophilias comprise a complex array of assays that may be unreliable in various settings, including acute thrombosis, inflammation, and uses of medications such as anticoagulants. The diagnostic yield of thrombophilia tests in unselected stroke patients is very low, but may improve with careful selection of younger patients who have an otherwise undetermined cause of stroke or a history of venous thrombosis or multiple miscarriages. Various strategies have been developed that can guide the selection of patients (based on specific characteristics) and tests in the evaluation of thrombophilias. Although the diagnosis of thrombophilia aids in the potential explanation of stroke etiology, the best regimen for secondary prevention treatment for the majority of thrombophilias is still unknown.