The production of antibodies by terminally differentiated plasma cells is the central humoral response that mediates host immunity to infections. Many plasma cells are short-lived and die by apoptosis after several days. Long-term production of antigen-specific antibodies is usually attributed to memory B cells. However, the central paradigm of plasma cell biology is changing with the discovery of long-lived plasma cells which contribute to life-long humoral immunity. Long-lived plasma cells have only been recognized as a part of immunological memory in the last decade – there is much to learn about the complexities of their development and survival. In this article, I review the extrinsic signals involved in long-lived plasma cell longevity, with an emphasis on how the bone marrow microenvironment contributes to the survival of long-lived plasma cells. Insights into these mechanisms will have a profound impact on plasma cell biology and provide novel therapeutic targets in autoimmune diseases and plasma cell malignancies.: © 2012 Liew. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and preproduction in any medium, provided the original author and source are credited. The main function of the immune response is to