The pleural fluid, owing to the manner of its formation in health and its limited range of response in disease, does not always lend itself to reductive analysis. This chapter incorporates a cohesive strategy for the laboratory diagnosis of pleural effusions. It examines the rationale for the various criteria/rules used for the discrimination of exudates from transudates, and discusses the differing conceptual approach between the two. It enumerates the clinical conditions that may be suspected on the basis of individual deviations in each of a number of biochemical parameters and examines the reasons for an apparent lack of consistency between cardinal biochemical parameters. Aetiologic possibilities are also discussed based on the type of cell that predominates in the pleural fluid, and the clinical relevance emphasised in each case.