Spermatozoa are comprised of many unique proteins not expressed elsewhere. Sperm-specific proteins are first expressed at puberty, after the development of immune tolerance to self-antigens, and have been assumed to remain confined inside the seminiferous tubules, protected from immune cell recognition by various mechanisms of testicular immune privilege. However, new data has shown that sperm-specific proteins are released by the tubules into the surrounding interstitial fluid; from here they can contact immune cells, potentially promote immune tolerance, and enter the circulation. These new findings have clinical implications for diagnostics and therapeutics targeted at a specific class of proteins known as cancer-testis antigens (CTA), the opportunity to identify new communication pathways in the testis, and to discover new ways to monitor testis function.