Plasma cell leukemia represents a unique subset of patients with multiple myeloma. The operational definition requires that the patient have a blood leukocyte count >10,000 and at least 2000 circulating plasma cells. This also must constitute 20% of circulating cells. Plasma cell leukemia is classified as primary when the initial diagnosis is with circulating cells and secondary when it occurs at the time of relapse. Extramedullary plasmacytomas can be either outside of the cortical bone or extension from the cortical bone and represent a high-risk form of multiple myeloma. This book chapter deals with the natural history, biology, clinical outcomes, and therapy of these two uncommon manifestations of multiple myeloma.