The treatment of newly diagnosed myeloma has evolved rapidly. The choice of initial therapy depends on eligibility for stem cell transplantation, as well as baseline risk factors. Eligibility for transplantation is important since the choice of initial therapy is primarily melphalan-based in patients who are not candidates for transplant, while melphalan-containing regimens are avoided as induction therapy in transplant candidates. An assessment of risk based on independent prognostic markers is important mainly for prognosis but may have some value in choice of initial therapy. For example, bortezomib-based regimens may have particular value in patients with certain high-risk features. This review discusses the current status of front-line therapy in younger patients with myeloma who are candidates for stem cell transplantation.