Effective radiation treatment of thoracic tumors is often limited by radiosensitivity of surrounding tissues. Several experimental studies have suggested variations in radiosensitivity of different pulmonary regions. Mice and rat studies in part contradict each other and urge for a more detailed analysis. This study was designed to obtain a more comprehensive insight in radiation injury development, expression, and its regional heterogeneity in lung. The latter is obviously highly critical for optimization of radiotherapy treatment plans and may shed light on the mechanisms of lung dysfunction after irradiation. Six different but volume-equal regions in rat lung were irradiated. Whereas the severity of damage, as seen in histologic analysis, was comparable in all regions, the degree of lung dysfunction, measured as breathing rates, largely varied. During the pneumonitic phase (early: 6-12 weeks), the most sensitive regions contained a substantial part of alveolar lung parenchyma. Also, a trend for hypersensitivity was observed when the heart lay in the irradiation field. In the fibrotic phase (late: 34-38 weeks), lung parenchyma and heart-encompassing regions were the most sensitive. No impact of the heart was observed during the intermediate phase (16-28 weeks). The severity of respiratory dysfunction after partial thoracic irradiation is likely governed by an interaction between pulmonary and cardiac functional deficits. As a repercussion, more severe acute and delayed toxicity should be expected after combined lung and heart irradiation. This should be considered in the process of radiotherapy treatment planning of thoracic malignancies.