Dietary nucleotides have been reportedly beneficial, especially for infants, since they positively influence lipid metabolism, immunity, and tissue growth, development and repair. Rapidly proliferating tissues, such as the immune system or the intestine are not able to fulfil the needs of cell nucleotides exclusively by de novo synthesis and they preferentially utilize the salvage pathway recovering nucleosides and nucleobases from blood and diet. In the present review we describe the modulatory effect of dietary nucleotides on the immune system together with some of their effects on gut-associated lymphoid tissue. Dietary nucleotides influence lymphocyte maturation, activation and proliferation. Likewise, they affect the lymphocyte subset populations in both the small intestine and blood. Moreover, they are involved in enhancing macrophage phagocytosis and delayed hypersensitivity as well as allograft and tumour responses. In addition, they contribute to the immunoglobulin response in early life, having a positive effect on infection. In fact the incidence and duration of acute diarrhoea is lower in infants fed supplemented-nucleotide formulas. The molecular mechanisms by which dietary nucleotides modulate the immune system are practically unknown. Dietary nucleotides have been shown to enhance the production and the genetic expression of IL-6 and IL-8 by foetal small intestinal explants. Dietary nucleotides may influence protein biosynthesis as well as signal membrane transduction mediated by the interaction of exogenous nucleosides and their receptors may also contribute to modulate the expression of a number of genes, some of which can directly affect the levels of intestinal cytokines.