Pathologic and laboratory investigations are essential when identification of the specific cause of bovine respiratory disease is needed. Considerations for planning a diagnostic investigation include the goals of the inquiry, the potential impact of the diagnosis, the plausible causes based on the clinical and epidemiologic appearance, and the relative merits of the available diagnostic strategies. This review uses 4 cases to outline different approaches to laboratory diagnosis. The postmortem examination is described, along with the patterns and gross appearance of lesions, considerations for effective sampling from appropriately selected animals, and reasons for discrepant or negative laboratory test results.