Cell growth and differentiation are highly controlled processes mediated by effector molecules, which are regulated by posttranslational chemical modifications. Adaptor molecules are critical players in these mechanisms because of their ability to simultaneously interact with multiple effector molecules and orchestrate the assembly of signaling complexes downstream of activated surface receptors. One family of adaptor molecules includes the CrkII/CrkL proteins that are also involved in the regulation of lymphocyte function. Although Crk proteins are amenable to regulation by protein tyrosine kinases, recent data suggest that peptidyl-prolyl cis-trans isomerases (PPIases) can alter their conformation and hence their ability to associate with binding partners. This emerging new function of PPIases is the subject of the current review.