The signalling loop concept was introduced in 1991 to explain activation of membrane and cytoplasmic kinases in response to DNA damage inflicted by ionizing radiation. Damage to the chromosomal DNA was thought to provide a primary signal and a secondary signal from a nucleus to cytoplasm was assumed. This scenario was confirmed although not as originally proposed. A complex of nuclear factor-kappaB (NF-kappaB) essential modulator and ataxia telangiectasia-mutated kinase activated by genotoxic agents is sent to cytoplasm, prompting nuclear translocation of the active transcription factor NF-kappaB. In parallel, linear signalling pathways are initiated in the cytoplasm, mostly by reactive oxygen species, resulting in NF-kappaB activation and nuclear translocation. The choice of NF-kappaB activation pathway and the extent of activation of various pathways may be influenced by the relative degree of damage inflicted by genotoxic agents in the nuclear and cytoplasmic compartments. The ultimate pattern of cellular response is determined by availability, abundance and localization of the proteins participating in the signal transduction.