Cyclophilin A (CypA) is a cytosolic binding protein of the immunosuppressive drug cyclosporin A. CypA has an activity of peptidylprolyl cis-trans isomerase, which may play important roles in protein folding, trafficking, assembly, immune-modulator and cell signaling. Secreted form of CypA can act as growth factors in several cell types. On the other hand, CypA also involves in pathogenesis in several diseases including viral infection, cardiovascular disease and cancer. For example, CypA protein displays an unusually high expression in several cancer types and correlates with poor outcome of the patients. In this review, we have focused on the recently available clinical data of altered CypA expression in various tumor tissues and cell lines and discussed contributions and potential molecular mechanisms of CypA to tumor progression and clinical association. CypA could promote cancer cell proliferation, anti-apoptosis, cell migration/invasion and drug resistant in various cancer cell types. The mechanism by which CypA contributes to cancer progression appears to involve a complex interplay of proteins and pathways including membrane receptor for CypA, CD147, and CypA binding partners inside the cells. CypA could be used as a molecular target for cancer therapy.