Standard frontline therapy for multiple myeloma comprises cytoreductive therapy with or without consolidative high-dose therapy plus stem cell transplantation (HDT-SCT). Despite therapeutic advances, the disease remains incurable; most patients relapse following frontline treatment and die within 5 years of diagnosis. New options are required to enhance and prolong response, and improve survival, particularly for elderly patients and those with renal dysfunction. Preclinical studies have demonstrated the ability of bortezomib to enhance the activity of commonly used myeloma agents, an observation validated through clinical studies in both the relapsed and frontline settings. This review focuses on the growing body of clinical evidence showing the effectiveness of bortezomib and bortezomib-based combinations in newly diagnosed patients, characterized by high overall response rates and consistently high rates of complete response. A number of studies incorporating bortezomib as part of induction therapy have demonstrated no adverse impact of bortezomib on stem cell harvest and engraftment in patients proceeding to transplantation. The higher rates of complete response typically associated with bortezomib treatment may potentially improve clinical outcomes in this setting. Final results from ongoing phase III studies of bortezomib-based combinations versus standard regimens will help define the optimal use of bortezomib as a standard component of frontline therapy for multiple myeloma. Disclosure of potential conflicts of interest is found at the end of this article.