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Multiple myeloma (MM), a heterogeneous plasma cell dyscrasia with a variety of clinical presentations and outcomes, is undergoing a treatment renaissance. While new drug classes have been discovered, a subset of high-risk MM remains relatively refractory to treatment. Current risk stratifications models, such as Durie-Salmon and the International Staging System, estimate disease burden and prognosis. Cytogenetics and gene expression profiles can help further identify more aggressive disease. Additionally, molecular and immunophenotypic assessment of minimal residual disease (MRD) and different imaging studies can identify patients at higher risk for relapse. It is now an opportune time to develop algorithms to combine all of the currently available clinical and genomic information to begin to inform specific therapeutic intervention in individual patients or at least smaller subgroups with similarly behaving disease.