Chest radiography is the most widely used medical imaging modality in the world. The volume of chest radiographic studies continues to rise, in tandem with increased utilization of cross-sectional imaging studies. The most efficient method of interpreting such a large and growing work volume requires a systematic approach applied in a consistent manner. Within that framework, challenging and unusual cases will arise and require more concentrated efforts than those needed to interpret the more typical cases in day-to-day practice. A challenge may arise due to small size or poor conspicuity of a pulmonary nodule on chest radiography—a nodule that may represent a lung cancer. That challenge can be met by the radiologist’s awareness of common causes for missing such lesions on radiographic studies. Other cases may be challenging by unusual combinations of imaging findings that may be manifestations of more than one underlying diagnosis. In other instances, the complexity and distribution of findings—as in cases of interstitial lung disease—may challenge the radiologist’s fund of knowledge and level of experience. The following cases illustrate teaching points that are intended to assist the reader in meeting such challenges.