Mitogen-activated protein kinases (MAPKs) and stress-activated protein kinases (SAPKs) respond to many extracellular signals, but the large number of these enzymes and their overlapping specificities in vitro has made it extremely difficult to identify the physiological roles and substrates of individual family members. This review discusses recent progress in understanding some of the functions of these enzymes that has been made possible by the introduction of some novel approaches, particularly the use of two specific inhibitors.