The approach to the patient with relapsed or relapsed/refractory multiple myeloma requires a careful evaluation of the results of previous treatments, the toxicities associated with it, and an assessment of prognostic factors. The majority of patients will have received prior therapy with drug combinations, including a proteasome inhibitor and an immunemodulatory agent. It is the physician's task to choose the right moment for the start of therapy and decide with the patient which goals need to be achieved. The choice of regimen is usually based on prior response, drugs already received, adverse effects, comorbidities of the patient, and expected efficacy and tolerability. Many double and triple drug combinations are available. In addition, promising new drugs such as pomalidomide, carfilzomib, and monoclonal antibodies are or will be available shortly, and other options can be explored in clinical trials. Finally, supportive care and palliative options need to be considered in later relapsed disease. Increasingly, it becomes important to consider the therapeutic options for the whole duration of the disease and integrate a systematic approach for the patient.