There has been a paradigm shift in the treatment of myeloma triggered by intense exploration of the disease biology to understand the basis of disease development and progression and the evolution of newly diagnosed myeloma to a multidrug refractory state that is associated with poor survival. These studies have in turn informed us of potential therapeutic strategies in our ongoing effort to cure this disease, or at a minimum convert it into a chronic disease. Given the clonal evolution that leads to development of drug resistance and treatment failure, identification of specific genetic abnormalities and approaches to target these abnormalities have been on the top of the list for some time. The more recent studies examining the genome of the myeloma cell have led to development of umbrella trials that assigns patients to specific targeted agents based on the genomic abnormality. In addition, other approaches to targeting myeloma such as monoclonal antibodies are already in the clinic and are being used in all stages of disease, typically in combination with other therapies. As the therapeutic strategy evolves and we have a larger arsenal of targeted agents, we will be able to use judicious combination of drugs based on specific tumor characteristics assessed through genomic interrogation or other biologic targets. Such targeted approaches are likely to evolve to become the mainstay of myeloma therapies in the future.