Significant advances in our understanding of the biology of multiple myeloma have led to exciting new opportunities in treatment. The management of this disease is rapidly changing with a plethora of clinical trials initiated with novel agents, namely thalidomide, lenalidomide and bortezomib, either alone or in conjunction with established modalities such as conventional cytotoxic agents and stem-cell transplantation. The combination of these novel agents together with conventional regimens have led to higher response rates and survival, providing options for patients whose disease is otherwise resistant to conventional therapy. These pivotal trials that lead to the approval of these three novel agents in treatment naïve patients. The potential implications in the frontline treatment paradigm of multiple myeloma are discussed.