Cyclophilins are originally identified as cellular binding proteins for the immunosuppressive drug cyclosporin A. Many cyclophilins, including CypA, CypB, CypC, CypD, and Cyp40, have been discovered and shown to be ubiquitously distributed in many types of cells and organ systems. Recent investigations have uncovered many important properties and functions for cyclophilins including peptidyle-prolyl-isomerase activity and protein folding/repair; maintaining mitochondrial functions and involvement in apoptosis; roles in regulation of T-cell function and inflammation; interaction with CD147; and pathogenesis of vascular disease, human immunodeficiency virus infection, and rheumatoid arthritis. Furthermore, the expression and functions of cyclophilins may be correlated with tumor biology of several types of cancers including pancreatic carcinoma. Molecular mechanisms of cyclophilin-mediated biologic events and future directions of research are discussed in this review. Understanding the roles of cyclophilins in cancers and other organ systems will be crucial in determining clinical applications for the treatment or diagnosis of human diseases.