Thalidomide (Thal) has antiangiogenic and immunomodulatory activity. Clinical research provided clear evidence that Thal is one of the most active drugs for the treatment of multiple myeloma leading to decrease of monoclonal protein of at least 50 % in 30 % of patients with relapsed or refractory multiple myeloma. Randomized trials based on a large body of evidence from phase II trials determined that Thal significantly increases total response rate in combination regimens (dexamethasone [Dex] and or chemotherapy) for relapsed as well as newly diagnosed patients. Thal also decreases time to response in combination therapy approaches. Thal has therefore been recognized by leading organizations as part of the treatment concept for patients with relapsed or refractory disease. Strict guidelines apply for the treatment and monitoring of Thal therapy to prevent the teratogenic effects of Thal and to monitor and prevent other potential adverse events as neuropathy and thrombosis. Additional randomized studies will now define the status of Thal for newly diagnosed patients and will be the basis for the approval in Europe and other countries world wide.