Multiple myeloma is a major hematologic malignancy, with an incidence of over 20,000 new diagnoses in the United States each year. Historically, a lack of effective therapies led to a poor patient prognosis. However, the introduction of new agents over the past decade has improved the treatment landscape for these patients, resulting in improved responses and prolonged progression-free and overall survival. Unfortunately, though, nearly all multiple myeloma patients go on to experience relapsed disease. The definition of this progression has also evolved with a growing understanding of the biology of multiple myeloma as well how the disease responds to these newer agents. While refractory multiple myeloma is considered to be a disease that does not respond to a particular therapy, the new definition of relapsed and refractory multiple myeloma includes patients who show disease progression within 60 days of discontinuing therapy. These new definitions are an important consideration when interpreting both previously reported and ongoing clinical trial data. Another major issue in the management of relapsed and refractory multiple myeloma is how to treat patients after they no longer respond to thalidomide, lenalidomide, and bortezomib. Regarding this issue, a number of novel agents are now in clinical trial development; many of them show indications of significant activity, even in heavily pretreated patients. Thus, the introduction of these newer agents has the potential to again make a major impact on multiple myeloma patient outcomes.