The role of prostaglandins as mediators of gastrointestinal mucosal defence has been recognized for more than two decades. However, there is renewed interest in the potent actions of this group of fatty acids in modulating the mucosal immune system and inflammatory responses. Moreover, there is a rapidly growing body of evidence that nitric oxide is another important mediator of mucosal defence and the mucosal immune system. In this review, the effects of prostaglandins and nitric oxide on specific aspects of mucosal immunocyte function (e.g., mast cell reactivity) are reviewed, as is the evidence that these two groups of endogenous mediators cooperate in the modulation of mucosal defence.