Immune privilege was first explored in the late 1800s by van Dooremaal, and was then extended by Medawar in the mid 1900s to fit in with emerging concepts of transplantation immunology. Modern concepts and understanding of immune privilege come from subsequent studies produced by Medawar, Billingham, and Streilein. The exploitation of the model of anterior chamber immune deviation (ACAID) in mice has allowed us to look at both cellular and molecular mechanisms involved in the prevention of potentially damaging immune responses in such privileged sites. This review gives a historical perspective of the immune privilege research and provides up-to-date information of molecules, cells, and concepts newly recognized as contributing to tolerance induction induced in such specialized areas of the body. Evidence is given to support the idea that application of such information may lead to potential for therapeutic applications of ACAID mechanisms in prevention of progression of immune-inflammatory diseases in humans.