Idiopathic interstitial pneumonia (IIP) represents a diverse group of lung disorders with variable prognoses and responses to therapy. As the name implies, the etiology is unknown. In the more severe forms of IIP, such as idiopathic pulmonary fibrosis and acute interstitial pneumonia, no effective therapies have been identified. In this perspective, the spatiotemporal variability in the histopathology of these disorders is discussed. It is proposed that common etiologies or injurious agents may produce variable histopathological "reactions" in the lung due to complex interactions between the host (genetic/epigenetic factors, age) and environmental factors. Accurate clinical and biological phenotyping may be necessary to stratify or group patients who are most likely to respond to specific modes of therapy.