In this article, we review evidence supporting an activity-dependent biological pathway that incorporates numerous schizophrenia candidate genes with critical roles in the regulation of memory and LTD, and that culminates in activation of the immediate early gene transcription factor EGR3. The unique position of immediate early gene transcription factors, at the nexus between environmental events and regulation of the neuronal response to activity, makes them ideally suited to account for both the genetic and environmental contributions to schizophrenia. Here, EGR3 is linked to schizophrenia.