Arterial thrombosis is the leading causes of morbidity and mortality worldwide, whereas venous thrombosis is the most common preventable cause of hospital death. In either case, venous and arterial thrombosis should be considered autonomous entities, with only minor overlaps in terms of risk factors, predisposing conditions and pathogenesis. Besides the widespread perception of embolization originating from low-pressure venous system and triggering ischemic stroke or peripheral arterial occlusion, "paradoxical" thrombosis might also develop or occur within clinical or biological circumstances where the blood should be less predisposed to clot, and wherein this risk is mostly unpredictable or overlooked. In this article we review epidemiological evidence and potential pathogenetic mechanisms of paradoxical thrombosis developing during antithrombotic therapy with vitamin K antagonists and heparin (i.e. heparin-induced thrombocytopenia), or antiplatelet agents such as aspirin, glycoprotein IIb/IIIa inhibitors or clopidogrel, and mostly attributable to direct effect of the agent.