Extramedullary (EM) plasmacytomas (EMPs) that are not progression of intramedullary (IM) plasma cell myeloma (PCM) are usually indolent. In contrast, EM spread of IM PCM is associated with a poor prognosis. The recently introduced Durie-Salmon PLUS staging system includes EM disease in the poor prognosis category. One study noted an increase in EM disease both at diagnosis and during follow-up of PCM in 2000-2007 compared with previous years raising concerns that adoption of novel agents (thalidomide, lenalidomide and bortezomib) and greater use of hematopoietic cell transplantation (HCT) might be contributory to this. It is uncertain if this is a true increase or merely greater detection due to the increasing use of more sensitive imaging techniques (computerized tomography, magnetic resonance imaging and ¹⁸F-fluorodeoxyglucose positron emission tomography) or a reflection of the evolving natural history of PCM in an era when patients are living longer (median overall survival before 1996 was 29.9 months vs 44.8 months after 1996). Recent studies suggest there are important biological differences between PCM with or without EM spread that are offering clues that might explain the propensity for dissemination and a more aggressive clinical course. For example, EM relapse in PCM with and without deletion 13 was 30.8 vs 5.6%, suggesting the biology of a plasma cell subclone before HCT can affect the nature of the relapse after HCT. This article will explore the clinical, biological and treatment implications of EM spread of PCM. In addition, the impact of extramedullary disease on the outcomes of autologous and allogeneic HCT for PCM will be analyzed. Allogeneic HCT early in the course of high-risk PCM with EM disease is a consideration since graft vs myeloma effects may be essential to achieve maximal survival benefits.