Although survival of multiple myeloma patients has at least doubled during recent years, most patients eventually relapse, and treatment at this stage may be particularly complex. At the time of relapse, the use of alternative drugs to those given upfront is current practice. However, many new options are currently available for the treatment of relapsed multiple myeloma, including recently approved drugs, such as the second- and third-generation proteasome inhibitors carfilzomib and ixazomib, the immunomodulatory agent pomalidomide, the monoclonal antibodies daratumumab and elotuzumab and the histone deacetylase inhibitor panobinostat, but also new targeted agents are under active investigation (e.g. signal transduction modulators, kinesin spindle protein inhibitors, and inhibitors of NF-kB, MAPK, AKT). We here describe a new paradigm for the treatment of relapsed multiple myeloma. The final goal should be finding a balance among efficacy, toxicity, and cost and, at the end of the road, achieving long-lasting control of the disease and eventually even cure in a subset of patients.