Immunity to previously encountered diseases is provided in large part by memory T lymphocytes, which may be subdivided based on phenotypic and functional differences, as well as the specific cellular compartments in which these cells reside. The bone marrow (BM) is a unique microenvironment that supports robust proliferation and recall responses of both "central" and "effector" memory T cells, particularly within the CD8+ T cell subset. The recent identification within human BM of a population of CD8+ effector memory T cells with hybrid phenotype and enhanced cytotoxic function has important implications for the development of future immunotherapies. Using activated BM CD8+ memory T cells for adoptive transfer or targeting such cells with tailored vaccines may improve the ability of these classic modalities to produce potent and long-lasting antigen-specific responses, ultimately leading to clinically significant control of viral and malignant diseases.