Although optimal strategy for management of patients with suspected venous thromboembolism depends on local expertise and cost, diagnostic algorithms including clinical assessment and D-dimer have been validated in several trials. However, a new paradigm shift is emerging, giving an extended role of D-dimer measurement in clinical practice. D-dimer is a useful biomarker to help determine initial anticoagulant therapy in patients with thrombosis. Emerging evidence also endorses a 'predictive' role for raised D-dimer levels, since its measurement provides prognostic indications for a variety of conditions, including venous thromboembolism, disseminated intravascular coagulation, cardiovascular disease, infectious diseases, and cancer. Additional investigation is needed to clarify whether raised D-dimer is an epiphenomenon or it is actively involved in pathophysiology. Further studies are also required to establish whether D-dimer testing, alone or combined with other prognostic indicators, can be used to identify patient candidates for further triage and treatment. Nevertheless, the hazard(s) associated with raised D-dimer in plasma requires re-emphasis in the teaching of post-graduates, junior doctors and medical students, including the most effective treatments to inhibit clot spread and decrease the probability of further significant thrombotic incidents even in the absence of any 'detectable' thrombosis.