Irradiation perturbs the homeostatic network linking parenchymal, mesenchymal, and vascular cells within tissues. Normal communication between cells through soluble, matrix, and cell-associated ligands and receptors is altered so as to set in motion a seemingly inexorable series of events aimed at tissue regeneration and healing. In late responding normal tissues where cell death is not compensated for by rapid regeneration, this process unfortunately often culminates in symptomatic complications of radiation exposure. Cytokines and their receptors are prominent in driving the cascade of molecular responses using the balance between seemingly mutually antagonistic molecules to control and direct the healing processes. There is strong evidence from preclinical models for the importance of cytokine-driven pathways in late radiation damage and growing evidence in humans for their relevance to radiation-induced disease. This review aims to show some general aspects of the molecular torrents that drive responses in irradiated tissues before and during the development of late effects. It attempts to collate some of the findings from preclinical models of late lung, central nervous system, skin, and intestinal damage and from clinical studies in the belief that understanding how irradiation perturbs the cellular communication networks will allow rationale intervention for mitigating late radiation tissue damage and carcinogenesis.