Abstract Multiple myeloma is a plasma cell malignancy characterized by molecular and clinical heterogeneity. The outcome of the disease has been dramatically improved with the advent of new drugs in the past few years. However, even in this context of increasing therapeutic options, important challenges remain, such as accurately evaluating patients' prognosis and predicting sensitivity to specific treatments and drug combinations. Transcriptomic studies have largely contributed to help decipher multiple myeloma complexity, characterizing multiple myeloma subgroups distinguished by different outcomes. Microarrays and, more recently, RNA sequencing allow evaluation of expression of coding and noncoding genes, alternate splicing events, mutations, and novel transcriptome modifiers, providing new information regarding myeloma biology, prognostication, and therapy. In this review, we discuss the role and impact of gene expression profiling studies in myeloma. Clin Cancer Res; 22(22); 5434–42. ©2016 AACR. See all articles in this CCR Focus section, “Multiple Myeloma: Multiplying Therapies.”