The chest radiograph remains the first imaging modality for the approach to diffuse infiltrative lung disease (DILD), but, 23 years after its introduction, high-resolution CT (HRCT) is still considered the best imaging tool for the evaluation of the pulmonary interstitium and to diagnose and assess DILD. The introduction of multidetector computed tomography (MDCT) has provided the thoracic radiologist with a powerful tool with which to image the lung. Moreover MDCT has enabled radiologists to understand better the functional information contained within CT images of DILD. By focusing on the HRCT signs, patterns, and distributions of abnormalities, and mentioning the clinical aspects and the new recent advances in pulmonary imaging, in this article we provide an overview of a practical approach to the interpretation of the DILD.