Monoclonal antibodies have been developed to optimize treatment effects in various malignant and nonmalignant conditions, by selectively targeting key components of the underlying pathophysiologic processes. Rituximab, a chimeric anti-CD20 antibody has revolutionized treatment of malignant lymphomas, extending remission rates, diseasefree survival and overall survival, all achieved with minimal toxicity. Bevacizumab, a humanized monoclonal antiantibody with anti-angiogenetic properties through inhibition of vascular endothelial growth factor, was initially approved for the adjuvant treatment of metastatic colorectal cancer with promising results. Eculizumab, a selective inhibitor of the complement terminal cascade, was the first etiologic treatment of intravascular hemolysis in patients with the rare, acquired paroxysmal nocturnal hemoglobinuria (PNH). Although none of these agents has direct antithrombotic properties, there is increasing evidence of their preemptive and therapeutic use in rare acquired thrombotic disorders, including thrombotic thrombocytopenic purpura (TTP), central retinal vein occlusion (CRVO) and PNH-associated thrombophilia. This brief review aims to discuss hopes and pitfalls of these new approaches in the context of the underlying mechanisms that lead to thrombosis in these disorders.