D‑Dimers derive from degradation of cross‑linked fibrin by plasmin, and thus their level is a marker of coagulation and fibrinolytic system activation. Guidelines recommend that D‑dimers are determined if the pretest probability (PTP) is low or intermediate, to exclude venous thromboembolism (VTE), either deep vein thrombosis or pulmonary embolism, and to avoid imaging tests. If the PTP is high or D‑dimer level is above the suggested thresholds, imaging is recommended. D‑Dimer assays offer high sensitivity and low specificity, as D‑dimer levels can be above the threshold in several other conditions than thrombosis, and they increase with age. As a result, there have been several proposals to improve the diagnostic accuracy of D‑dimer levels by adjusting the cutoffs according to patient characteristics, such as age, PTP, pregnancy, renal function, or cancer. D‑Dimer levels can also predict clinical severity of COVID‑19, and escalated anticoagulation based on D‑dimer levels can be associated with a lower risk of mortality in patients with severe COVID‑19. Finally, D‑dimer levels have been incorporated in prediction models for recurrent VTE to help identify patients who may benefit from prolonged anticoagulation.