The mitogen-activated protein kinase (MAPK) cascade has been intensely studied as a primary biochemical pathway through which a variety of extracellular stimuli initiate and regulate processes of cellular transformation. That MAPKs are abundantly expressed in postmitotic neurons, however, suggests different yet currently unknown functions for this cascade in the mature nervous system. Here we report that the MAPK cascade is required for hippocampal long term potentiation (LTP), a robust and widely studied form of synaptic plasticity. We observed that PD 098059, a selective inhibitor of the MAPK cascade, blocked MAPK activation in response to direct stimulation of the NMDA receptor as well as to LTP-inducing stimuli. Furthermore, inhibition of the MAPK cascade markedly attenuated the induction of LTP. PD 098059, however, had no effect on the expression of established LTP, and the MAPK cascade was not persistently activated during LTP expression. Our observations provide the first demonstration of a role for the MAPK cascade in the activity-dependent modification of synaptic connections between neurons in the adult mammalian nervous system.