A major question in the process of dendrite development and complexity is not whether neuronal activity plays a role, but how it contributes to specific components of the mature dendrite pattern. Neurons interpret activity into the influx of calcium ions leading to activation of signaling pathways. The dynamics of calcium-activated signaling pathways after neuronal activity and the contribution to formation of dendrite complexity remain unclear. Here, we show that one calcium activated signaling pathway, extracellular signal-regulated kinase (ERK), showed differential activity in cortical neurons. In response to depolarizing stimuli, ERK was active for less than an hour in most neurons, whereas in others ERK remained active for several hours. Further, neurons in which ERK activity was sustained, displayed greater dendrite complexity than neurons that did not display sustained ERK activity. Interestingly, this difference in dendrite complexity was detected in some, but not all, morphological parameters. Pharmacological inhibition of sustained ERK activity inhibited calcium-activated dendrite complexity. Increasing the duration and degree of ERK phosphorylation, and thus activity, with dominant negative MAP kinase phosphatase-1 accentuated dendrite complexity. Neurons in which ERK activity was sustained activated downstream nuclear targets including RSK, MSK, cAMP response element binding protein (CREB), CRE-mediated gene transcription, and stabilized c-Fos. Further, the increase in dendrite complexity mediated by sustained ERK activity was inhibited by expression of a dominant negative CREB. These data indicate that ERK-mediated activity induced dendrite complexity via sustained signaling and CREB-mediated signaling. © 2008 Wiley Periodicals, Inc.