Under the model of spatial or tissue-specific immune compartmentalization, the site of immunogen exposure (oral, mucosal and dermal) shapes the consequent immune response. Thus, spatial compartmentalization provides a mechanism whereby different immune responses may evolve in different tissue compartments. Many immune cytokines are subject to circadian variation, for example, interleukin-1, -6, -10 and -12, macrophage migration inhibitory factor, tumor necrosis factor-alpha and interferon-gamma. These cytokine rhythms reflect the influence of regulatory hormones including cortisol and melatonin that exhibit circadian rhythmicity. This raises the question of what role, if any, circadian rhythms play in immune function. The hypothesis put forward is that circadian cytokine rhythms indicate the existence of temporal immune compartments. Temporal immune compartments include a daytime compartment characterized by high plasma cortisol and a regulatory cytokine environment, and a nocturnal compartment characterized by low cortisol, high melatonin and heightened inflammatory cytokine levels. Thus, time itself is a critical factor when measuring or interpreting immune response. This highlights the potential of immune chronotherapy where time-dependency principles guide the design of more effective and better tolerated immunotherapies and vaccines.