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Despite the fact that cyclosporin A (CsA) and tacrolimus (FK506) are very potent drugs in the treatment of serious autoimmune diseases and in the prevention of graft vs. host reactions or tissue rejections after allo- or xenotransplantations, modern transplantation medicine attempts to develop alternative medication regimes without these calcineurin inhibitors. The primary motivation for this endeavor is the high incidence of dramatic side effects upon immunosuppressive therapy. CsA and FK506 target not only the calcineurin/NFAT pathway, but they also bind and inhibit members of distinct peptidyl-prolyl cis/trans isomerase families, which are involved in numerous important signal transduction pathways. Therefore, the development of a potent calcineurin inhibitor that discriminates between calcineurin and other protein phosphatases and peptidyl-prolyl cis/trans isomerases, respectively, should improve the drug safety in clinical use and represent a valuable tool in basic research to investigate calcineurin modulated pathways. This review gives a current overview about novel calcineurin inhibitors, which were identified by screening of compound libraries and in natural materials or were derived from known inhibitors in the past decades. Thereby, we focus on their structure, properties and biological effects.