There is increasing evidence that the supportive cells (stromal cells) in nearly all organs containing cellular self-renewal systems are involved in carcinogenesis. One body of evidence specific to irradiation leukemogenesis documents the role of irradiated murine stromal cells in the cell biologic changes associated with evolution of leukemia in cocultivated, nonirradiated stem cells. Stem cell phenotypic changes that have been documented include upregulation of cell surface c-fms, downregulation of growth requirement for obligatory growth factors, and the appearance of novel transcripts detected by differential display. A second body of evidence documents the potential role of stromal cells functioning as biologic tumor promoters through their release of reactive oxygen species (ROS), and production of altered adhesion molecules or growth factors during the chronic response to chemical or physical carcinogens. These molecular biologic mechanisms, potentially operative in stromal cells, can block apoptosis and induce DNA strand breaks in closely associated self-renewing stem cells. In an in vivo model of irradiation effects on lung stromal cells, we have irradiated the lungs of control C57BL/6J mice or other mice with orthotopic Lewis lung tumors and shown that TGF-beta release is increased following irradiation. The TGF-beta increase by irradiation may specifically be inhibited by administering an inhalation plasmid liposome mixture containing a transgene for human manganese superoxide dismutase prior to irradiation. An appreciation of the role of stromal cells in leukemogenesis and carcinogenesis may also be very relevant to the design of new therapeutic strategies for treatment of cancer, particularly since current strategies focus on eradication of stem cell transformants and do not rigorously address the persistence of surviving stromal cells.