The administration of lithium followed by pilocarpine induces status epilepticus (SE) that produces neurodegeneration and the subsequent development of spontaneous recurrent seizures. We have reported that tyrosine phosphorylation of the NMDA receptor is elevated over controls for several hours following 60 min of SE. In the current study, we assessed the temporal relationship between tyrosine phosphorylation of the NMDA receptor and the onset of SE. SE was induced using the Li/pilocarine model and phosphorylation of the NMDA receptor subunits NR2A and NR2B determined. Tyrosine phosphorylation of the NMDAR remained unchanged prior to the onset of SE and increased gradually thereafter. The onset of SE was accompanied by activation of Src-family tyrosine kinases and Pyk2 in the post-synaptic density, consistent with a role for these enzymes in SE-induced tyrosine phosphorylation. The results indicate that tyrosine phosphorylation of the NMDAR closely parallels the activation of Src-family kinases and follows, rather than precedes, the onset of SE.