Patients with derangements of secondary hemostasis resulting from inherited or acquired thrombophilias are at increased risk of venous thromboemboli (VTE). Evaluation of a patient with suspected VTE proceeds via evidence-based algorithms that involve computing a pretest probability based on the history and physical examination; this guides subsequent work-up, which can include D dimer and/or imaging. Testing for hypercoagulable disorders should be pursued only in patients with VTE with an increased risk for an underlying thrombophilia. Direct oral anticoagulants are first-line VTE therapies, but they should be avoided in patients who are pregnant, have active cancer, antiphospholipid antibody syndrome, severe renal insufficiency, or prosthetic heart valves.