This review brings available data together to put in perspective the binding properties of high molecular weight kininogen (HK) to cytokeratin 1 (CK1) to direct future investigations. We summarize our knowledge of the structure and function of HK and discuss the influence of HK on the biologic activities of the plasma kallikrein/kinin system. To better understand the role of HK in regulating the activation of the kallikrein/kinin system, we discuss the interaction of HK with endothelial cell CK1 and its influence on prekallikrein activation. Last, we address the question on how a cytoskeletal protein could be a membrane-binding site and its possible role in disease states.