Making a diagnosis of deep vein thrombosis (DVT) requires both clinical assessment and objective testing because the clinical features are nonspecific and investigations can be either falsely positive or negative. The initial step in the diagnostic process is to stratify patients into high-, intermediate-, or low-risk categories using a validated clinical model. When the clinical probability is intermediate or high and the venous ultrasound result is positive, acute symptomatic DVT is confirmed. Similarly, when the probability is low and the ultrasound result is normal, DVT is ruled out. A low clinical probability combined with a negative D-dimer result can also be used to rule out DVT, thereby obviating the need for ultrasonography. In contrast, when the clinical assessment is discordant with the results of objective testing, serial venous ultrasonography or venography is required to confirm or refute a diagnosis of DVT. Once a patient is diagnosed with an acute DVT, low-molecular-weight heparin (LMWH) is the agent of choice for initial therapy and oral anticoagulant therapy is the standard for long-term secondary prophylaxis. Therapy should continue for at least 3 months; the decision to continue treatment beyond 3 months is made by weighing the risks of recurrent thrombosis and anticoagulant-related bleeding, and is influenced by patient preference. Screening for associated thrombophilia is not indicated routinely, but should be performed in selected patients whose clinical features suggest an underlying hypercoagulable state. Several new anticoagulants with theoretical advantages over existing agents are undergoing evaluation in phase 3 studies in patients with venous thromboembolism.