Thrombosis is a frequent feature in individuals with myeloma, particularly those treated with oral immunomodulatory drugs (IMID) such as thalidomide or lenalidomide concomitantly with anthracyclines or dexamethasone. Up to a third of these individuals may develop venous thrombosis if not given the benefit of prophylaxis. Interestingly, in contrast to individuals with solid tumors in whom thrombosis is a marker of poor prognosis, thrombosis does not impact overall survival in patients with myeloma. This finding suggests that the mechanisms of thrombosis in hematological neoplasms may differ from solid epithelial tumors and that thrombosis in the former may be driven by therapy and not by a procoagulant phenotype of the neoplastic plasma cells. This may also explain why thrombosis in the context of IMID-based therapy may be prevented by the use of prophylactic aspirin. In this text, we review the pathogenesis of thrombosis in myeloma, its relation to different chemotherapeutic regimens and the use of thrombo-prophylaxis.