D-dimer is a fibrin degradation product encompassing multiple cross-linked D domains and/or E domains present in the original fibrinogen molecule, whose generation is only theoretically possible when hemostasis and fibrinolysis pathways are concomitantly activated. D-dimer measurement has now become a pillar in the diagnosis/exclusion and prognostication of venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC), when incorporated into validated clinical algorithms and especially using age-adjusted diagnostic thresholds. Although emerging evidence is also supporting its use for predicting the duration of anticoagulant therapy in certain categories of patients, the spectrum of clinical applications is constantly expanding beyond traditional thrombotic pathologies to the diagnosis of acute aortic dissection, acute intestinal ischemia and cerebral venous thrombosis among others, embracing also clinical management of coronavirus disease 2019 (COVID-19). Recent findings attest that D-dimer elevations are commonplace in patients with severe acute respiratory syndrome (SARS-CoV-2) infection (especially in those with thrombosis), its value predicts the clinical severity (up to death) of COVID-19 and remains more frequently increased in COVID-19 patients with post-discharge clinical sequelae. Further, D-dimer-based anticoagulant escalation may be associated with a lower risk of death in patients with severe SARS-CoV-2 infection and, finally, D-dimer elevation post-COVID-19 vaccination mirrors an increased risk of developing vaccine-induced thrombocytopenia and thrombosis (VITT).