Multiple Myeloma is a plasma cell malignancy with complex genetic and epigenetic alterations. Comprehensive oncogenomic analysis has improved our understanding of molecular pathogenesis of MM identifying highly recurrent and focal amplifications/deletions. Whole genome sequencing has identified on an average over 50 mutations per patient; however except for N-ras, K-ras and B-raf mutations, no other mutation has frequency greater than 10%. We have identified diverse processes including kataegis and somatic hypermutation that lead to the observed mutational repertoire. Analysis of serial samples have recognized ongoing genomic evolution utilizing various patterns such as linear or branching evolution or differential clonal response with presence of subclonal driver mutations. This observed significant heterogeneity between and within patients is driven by tumor inherent features and/or response to therapy. These data on mutational repertoire along with ongoing accumulation of data describing myeloma trancriptome as well as transcriptome modifiers such as alternate splicing and microRNA profiling using clinically annotated patient samples have allowed for better understanding of molecular mechanism of the disease behavior, developing predictive prognostic models, and identifying novel therapeutic targets. The ongoing efforts are targeted at overcoming effects of mutations such as Ras or Raf; inhibiting influence of overexpressed genes such as DKK-1, Btk, Dp1 or CRM1 amongst others; and modifying activity of epigenomic writers and erasers such as MMSET, bromodomain and extra-terminal (BET) domain family of proteins or HDACs. These studies are now providing the framework to develop molecularly-based single and combination therapies and eventually a personalized therapeutic approach to improve outcome in myeloma.