The age-related decrease in immunologic function is believed to be the major predisposing factor contributing to increased morbidity and mortality with age. Hence, the restoration of immunologic function is expected to have a beneficial effect in reducing pathology and maintaining a healthy condition in advanced age. Among various intervention strategies, caloric restriction (CR) has been shown to be the most powerful modulator of aging process. It is the most efficacious means of increasing longevity and reducing pathology. Several mechanisms have been proposed to explain its beneficial and robust action on various physiological systems, including the immune system. Experimental evidence suggests that CR increases longevity and reduces pathology through its action on the immune system. The observation that CR attenuates immunosenescence has provided a rationale for studying whether CR exerts its action through modulation of gene expression. The available data indicate that the effect of CR on signal transduction and gene expression can vary considerably from gene to gene and from one signaling molecule to another. This review summarizes the studies on the influence of CR on aging immune system and discusses the current state of knowledge on the molecular mechanisms responsible for the immunomodulatory action of caloric restriction.