Multiple myeloma is a heterogeneous disease with complex genetics, including a variety of primary and secondary genetic events that contribute to disease pathogenesis. Good risk genetics include hyperdiploidy (approximately 40%) and cyclin D translocations (t[11;14] and t[6;14]; approximately 18%). Poor risk genetics include t(4;14), approximately 15%; MAF translocations (t[14;16]) and t[14;20]; approximately 8%); secondary genetic events such as deletion p53, and abnormal cytogenetics (deletion 13 or hypodiploidy). Proliferation is the other poor risk feature, as measured by either plasma cell labeling index, beta(2)-microglobulin, or gene expression profiling; it is identified in all genetic subtypes and not yet captured by any genetic marker. Altogether, approximately 75% of patients are good risk and if eligible, do well with high-dose melphalan and autologous stem cell transplantation. In contrast, about 25% of the patients have poor risk features and receive only transient benefit from this approach. We propose the Mayo Stratified Myeloma and Risk-Adapted Therapy. Stem cell transplantation is deferred in patients with high-risk molecular markers, and in all patients, response is followed closely and determines the individual timing and sequence of therapeutic regimens.