Ca²⁺ influx through NMDA receptors can initiate molecular changes in neurones which may underlie synaptic plasticity, neuronal development, survival and excitotoxicity. Signalling through the MAP kinase (Erk1/2) cascade may be central to␣these processes. We previously demonstrated that Ca²⁺‐permeable AMPA receptors activate Erk1/2 through a phosphatidylinositol 3‐kinase (PI 3‐kinase)‐dependent mechanism. We now report that NMDA receptor activation of Erk1/2 was also blocked by inhibitors of PI 3‐kinase (LY 294002, wortmannin). In addition, pre‐treatment of neurones with pertussis toxin inhibited NMDA‐induced Erk1/2 activation, indicating a role for heterotrimeric G_i/o proteins. PI 3‐kinase directs activation of the serine‐threonine kinase Akt (PKB). Treatment of striatal neurones with glutamate induced a rapid Ca²⁺‐dependent and PI 3‐kinase‐dependent phosphorylation of Akt (Ser473), which was not blocked by the Mek inhibitors PD98059 or U0126. Targets for Erk1/2 and Akt pathways include transcription factors. Glutamate‐induced phosphorylation of cAMP response element binding protein (CREB; Ser133) was partially blocked with either PD98059, U0126, LY294002 or wortmannin but was very strongly inhibited on co‐application of LY294002 and PD98059. We propose that NMDA receptor stimulation can activate Erk1/2 and Akt signalling pathways in a PI 3‐kinase dependent manner which may target CREB in the nucleus.