The recent emergence of SARS-CoV-2 and the ensuing global pandemic has presented a health emergency of unprecedented magnitude. Recent clinical data has highlighted that COVID-19 is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease and stroke. Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multi-organ failure and increased mortality. The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 is due to the ability of SARS-CoV-2 to invade endo¬thelial cells via angiotensin-converting enzyme 2 (ACE2), which is expressed on the endothelial cell surface. However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic compli¬cations such as deep vein thrombosis, pulmonary embolism and stroke. Accordingly, the activation of coagulation (e.g. as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19. Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance. A number of antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including, heparin, FXII inhibitors, fibrinolytic drugs, nafamostat and dipyridamole, many of which also possess pleiotropic anti-inflammatory or anti-viral effects. The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients is driving efforts to more stringent diagnostic screening for thrombotic compli¬cations and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications. The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.