Human cells have evolved several mechanisms for responding to damage created by ionizing radiation. Some of these responses involve the activation or suppression of the transcriptional machinery. Other responses involve the downregulation of enzymes, such as topoisomerase I, which appear to be necessary for DNA repair or apoptosis. Over the past five years, many studies have established links between DNA damage, activation of transcription factors that are coupled to DNA repair mechanisms, increased gene transcription and altered cell cycle regulation to allow for repair or cell death via apoptosis or necrosis. Together these factors determine whether a cell will survive with or without carcinogenic consequences. The immediate responses of human cells to ionizing radiation, in terms of sensing and responding to damage, are therefore, critical determinants of cell survival and carcinogenesis.