This study presents a model that explains the difference in radiosensitivity between dividing and resting mammalian non-lymphoid tissue cells (liver, kidney, respiratory tract, muscle cells, neurons), based on the topological organization of DNA. In dividing cells, the target for radiation might be identified in replicon clusters or domains (7 X 10(8)-5.8 X 10(9) Da of DNA), in contrast with resting cells, in which the target could be limited to the size of chromatin loops or replicons (10(7)-10(8) Da). Hence, the target theory, D37(cGy) = 0.58 X 10(12)/weight of DNA in Da, indicates that the D37 dose (low-LET radiation) needed to inactivate 63% of the replicon clusters contained by the genome is around 100-850 cGy, and the D37 doses that could damage 63% of chromatin loops increase to 5800-58,000 cGy, with a value of 10,000 cGy for medium size replicons (5.8 X 10(7) Da). Accordingly, most dividing cells have D37 doses of 35 to 650 cGy, and the D37 values for the interphase death of non-lymphoid resting cells increase to several tens of Gy or more. These data are consistent with the idea that killing of dividing cells is correlated with the inactivation of most replicon clusters (about 720-6000 domains per genome), induced mainly by DNA single-strand breaks (SSBs), associated with double-strand breaks (DSBs); while the death of resting cells occurs when the majority of replicons comprised by the cell nucleus (about 72,000 chromatin loops) are damaged by radiation (SSBs, DSBs), which might prevent the process of transcription.