Therapy-related lymphoid proliferations are well described in the setting of iatrogenic immunosuppress ion after transplantation. More recently, however, they have also been observed in patients being treated for a number of other conditions. This brief review will focus on 2 such scenarios, each with quite divergent pathogeneses and consequences. In therapy-related acute lymphoblastic leukemia, the typical setting is prior chemotherapy (typically topoisomerase II inhibitors) for an unrelated neoplasm, in which direct cytotoxic DNA damage is likely to be the primary cause. By contrast, those arising in the setting of autoimmune diseases are more heterogeneous, not always overtly neoplastic and mechanistically complex. This heterogeneity and complexity is based upon, among others, the nature of the underlying disease as well as the variability of different and sometimes sequential or concomitant therapeutic interventions.