Considerable progress has been made in elucidating genetic and biologic risk factors for venous thromboembolism (VTE). Despite being able to identify heritable defects in a substantial proportion of patients with VTE, testing has not, in general, proven useful in management. Despite efforts to reduce inappropriate testing, it often falls to the hematologist to consult on patients having undergone thrombophilia testing. Through a series of cases, we discuss how D-dimer testing can be helpful in VTE recurrence risk stratification in younger women as well as how to approach patients with persistently elevated D-dimer levels in the absence of thrombosis. While elevated factor VIII coagulant activity levels are a significant risk factor for a first episode of VTE, its biologic basis is not fully understood, and studies have not shown it to be a useful predictor of recurrence. Abnormal results of genetic tests for methylene tetrahydrofolate reductase or plasminogen activator 1 promoter polymorphisms may be encountered, which carry little if any thrombotic risk and should never be ordered. We also discuss protein S deficiency, the most difficult of the hereditary thrombophilias to diagnose due to a wider "normal" range in the general population as compared with protein C, the presence of both free and bound forms in plasma, and the characteristics of the various assays in use. We also present a rare type of protein C deficiency that can be missed by functional assays using an amidolytic rather than a clotting end point.