Cyclophilins are proteins which are remarkably conserved through evolution; moreover they have been found in every possible existing organism, which indicates their fundamental importance. Due to their enzymatic properties, multiplicity, cellular localization and role in protein folding they belong to the group of proteins termed molecular chaperones. All the proteins of the cyclophilin family possess enzymatic peptidyl-prolyl isomerase activity (PPI-ase), which is essential to protein folding in vivo. Recently PPI-ase activity was suggested as playing a role in regulation of transcription and differentiation. However, not all cyclophilin functions are explained by PPI-ase activity. For instance, one of the cyclophilins plays a regulatory role in the heat shock response and the mitochondrial cyclophilin (Cyclophilin D) is an integral part of the mitochondrial permeability transition complex, which is regarded as having a crucial role in mechanisms of cell death. In support of a role in the stress response, the expression of certain cyclophilins has recently been shown to be up-regulated under various stressful conditions. Current evidence of functional involvement of cyclophilins in various intracellular pathways is reviewed along with the indications that cyclophilin D (Cyp D) represents a crucial part of the mitochondrial permeability transition pore, which is detrimental in apoptotic and necrotic cell death. This review does not attempt to cover all the existing information related to cyclophilin family of proteins, but focus on the existing evidence of the involvement of these proteins in the intracellular stress response.