Compared with other organs, the lung is unique in its open connection with the outside world. Although various defense mechanisms are present, everything that passes through the airways is still a great influence, including environmental pollution, occupational exposure, and tobacco smoke. To a certain extent, these exposures themselves can cause pathology of the lung, but even more important may be the low-level exposures that, by themselves, do not cause clinically relevant pathology, but which do have profound effects on the microenvironment of the lung, most often by causing inflammatory changes. This means that often, the histopathologic picture is complicated by the confounding effects of such low-level exposures. Smoking is the most extensively known exposure in the population worldwide, followed by environmental pollution in the industrialized world (and, perhaps, exposure to fumes from indoor cooking in the nonindustrialized societies) and, somewhat less, by occupational exposure. These exposures will almost always affect the histopathologic presentation of lung pathology. Recent publications have shown that exposures like smoking also give rise to significant molecular changes (1-4) and, thus, will also affect research into the molecular background of pulmonary disease. As new therapeutic options based increasingly on molecular research emerge, confounding molecular effects, like those caused by smoking, become more and more relevant. The advances in knowledge about lung disease and the many recent developments in molecular pathology and molecular diagnosis, in general, might suggest that there will be a reduced demand for traditional pulmonary pathology in the future. As already argued recently by Andrew Nicholson, (5) however, the problem diagnostic areas have not really changed during recent years, and diagnostic referrals have not decreased. Likely, this is partly due to our still-limited understanding of many areas of lung pathology. In addition, as indicated above, lung pathology is complicated by a combination of etiologic effects that result in complex histopathologic patterns, often further complicated by intricate clinical presentations and radiology. This is particularly the case for nonneoplastic lung pathology. Another confounding factor is that the lung has a large reserve capacity with respect to lung function. Therefore, diagnostic procedures are typically performed after disease has already progressed for quite some time (depending on the extent to which patients have already used their lung capacity). Such long-standing damage to the lung often results in a more or less common, final pathway for different diseases, with fibrotic and inflammatory changes, so that it is not always easy to discern the specific underlying etiology or disease entity.