Front-line therapy for multiple myeloma is rapidly evolving with the development of new, highly active regimens based on novel agents such as bortezomib. Bortezomib-based regimens are demonstrating substantial efficacy both as induction prior to stem cell transplantation and as treatment for patients ineligible for transplant, offering rapid and durable responses with consistently high rates of complete response, a surrogate end point for improved overall survival. Combinations of bortezomib plus established and novel agents, such as melphalan-prednisone, dexamethasone, doxorubicin, thalidomide-dexamethasone and, most recently, lenalidomide-dexamethasone, are proving superior to or more promising than previous standards of care. Importantly, these regimens are demonstrating enhanced activity across the front-line population, including patients with renal impairment, high-risk cytogenetics and advanced bone disease. Impressive Phase 3 results with bortezomib-melphalan-prednisone, bortezomib-dexamethasone and bortezomib-thalidomide-dexamethasone should facilitate the establishment of these highly effective regimens as key therapies for newly diagnosed myeloma.