The term 'immune privilege' (IP) generally describes the protection of vital structures, such as the brain, the eye, or the pregnant uterus, from the potentially damaging effects of an inflammatory immune response. Initially, barriers physically camouflaging such organs were thought to shield autoantigens from immune recognition and inflammation. This simplistic concept gave way to a much more complex understanding of IP, which reflects an entire network of interacting immunoregulatory processes and immunosuppressive microenvironments. Also, the number of organs and tissues that enjoy relative IP has grown considerably. This is not surprising since many different organs are constantly exposed to major, potentially damaging inflammatory events, for example, skin, gut, or lung-without evidence for excessive inflammation under physiological conditions. Focusing on fetotrophoblast IP as well as on hair-follicle-associated IP (an underappreciated, yet biologically fascinating, clinically important IP model), we summarize here key regulatory cues that operate in immunoprivileged tissues. Proposing novel concepts of how IP may collapse, for example, by exposure to psychosocial, stress-associated inflammation, we develop related strategies for how IP may be manipulated clinically so as to achieve IP protection and restoration. © 2008 Elsevier Ltd. All rights reserved.