Venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism, is a major cause of morbidity and mortality worldwide, and represents a time‑sensitive clinical condition where diagnostic delay increases unfavorable outcomes. Among the various laboratory biomarkers investigated to support the diagnosis of VTE, D‑dimer has emerged as the reference test for excluding acute thrombosis when interpreted within an appropriate clinical framework. D‑dimer is a fibrin degradation product generated during plasmin‑mediated breakdown of cross‑linked fibrin, reflecting concurrent activation of coagulation and fibrinolysis. Modern diagnostic strategies integrate D‑dimer testing with structured assessment of pretest probability using validated clinical decision tools, such as the Wells score, the Revised Geneva Score, and the Pulmonary Embolism Rule‑out Criteria. In patients with low or intermediate clinical probability, a negative D‑dimer result can safely exclude VTE and avoid unnecessary imaging, whereas elevated values or high clinical suspicion require confirmatory imaging. Recent developments, including age‑adjusted D‑dimer thresholds and probability‑adapted algorithms, such as the YEARS and Pulmonary Embolism Graduated D‑dimer, have improved diagnostic specificity and reduced reliance on imaging techniques without compromising patient safety. Nevertheless, the clinical reliability of D‑dimer testing is influenced by preanalytical variables, assay‑related differences, and presence of physiological or pathological conditions associated with elevated or low fibrin turnover. Accordingly, optimal use of D‑dimer testing requires strict laboratory supervision and integration with clinical probability assessment to ensure accurate and timely diagnosis of VTE.