In general, transudates have a systemic cause, whereas the cause for exudates is most often regional. Bilateral pleural effusions are more frequently transudates than exudates. The reverse is true of unilateral pleural effusions. Thus, the approach to unilateral and bilateral pleural effusions conceptually differs. This chapter outlines the diagnostic approach to the unilateral pleural effusion. It lists the questions to ask while seeking the cause of a unilateral pleural effusion and systematically presents the aetiologic possibilities, describing the pleural fluid characteristics in each case. It also discusses unusual situations such as unilateral pleural effusions that are transudative, and examines the conditions responsible for the same.