Although upfront treatment of multiple myeloma has become more effective, relapses are the norm, often driven by the emergence of a genetically divergent clone selected by the initial therapy. Recent trials have demonstrated the safety and efficacy of combination therapy also in the relapsed and refractory setting and supported the regulatory approval of several new agents including new proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. We provide a detailed summary of recent practice-changing trials in relapsed and refractory MM and share a practical approach to assimilate disease and patient-features into treatment decision. Am. J. Hematol. 91:1044–1051, 2016. © 2016 Wiley Periodicals, Inc.