The central hypothesis of our laboratory research program in large granular lymphocyte (LGL) leukemia is that leukemic LGL represent antigen-driven cytotoxic T lymphocytes (CTL) with characteristics of dysregulated apoptosis. The clinical features of LGL leukemia highlight the association of autoimmune diseases such as rheumatoid arthritis with the T-cell form of LGL leukemia. We therefore used LGL leukemia as a model disease of dysregulated apoptosis leading to both malignant and autoimmune diseases. Here, we review our understanding of survival signals activated in leukemic LGL in the context of knowledge concerning apoptotic pathways in activated normal lymphocytes.