Exposure to ultraviolet (UV) radiation, as in sunlight, can modulate immune responses in animals and humans. This immunomodulation can lead to positive health effects especially with respect to certain autoimmune diseases and allergies. However, UV-induced immunomodulation has also been shown to be deleterious. Experimental animal studies have revealed that UV exposure can impair the resistance to many infectious agents, such as bacteria, parasites, viruses, and fungi. Importantly, these effects are not restricted to skin-associated infections, but also concern systemic infections. UV radiation induces a multistep process, locally in the skin as well as systemically, that ultimately leads to immunosuppression. The first event is the absorption of "UV" photons by chromophores, or so-called photoreceptors, such as DNA and urocanic acid (UCA) in the upper cell layers of the skin. Upon absorption of UV radiation, trans-UCA isomerizes to the cis-isomer. Cis-UCA is likely the most important mediator of UV-induced immunosuppression, as this compound has been shown to modulate the induction of contact type hypersensitivity and delayed type hypersensitivity, allograft rejection, and the functions of monocytes and T-lymphocytes as well as natural killer cells. The real consequences of UV-induced immunomodulation on resistance to infectious diseases for humans are not fully known. Risk estimations have been performed through extrapolation of animal data, obtained from infection models, to the human situation. This estimation indicated that UV doses relevant to outdoor exposure can impair the human immune system sufficiently to have effects on resistance to infections, but also indicated that human data are necessary to further quantify and validate this risk estimation. Further information has been obtained from vaccination studies in human volunteers as ethical reasons prohibit studies with infectious agents. Studies in mice and human volunteers on the effects of prior UVB exposure on hepatitis B vaccination responses revealed suppressed cellular and humoral immune responses in mice but not in human volunteers. However, subgroups within the performed human volunteer study made by determination of cytokine polymorphisms or UVB-induced mediators, revealed that some individuals have suppressed hepatitis B vaccination responses after UVB exposure. Thus, it might be concluded that the human immune system can be affected by UVB exposure, and decreased resistance to infectious diseases can be expected after sun exposure.