There is no doubt that synaptic activity-regulated expression of immediate early genes (IEGs) contributes to long-lasting changes in neural functions, including learning and memory. Consequently, dysregulation of IEG expression has been involved in the conditions of neural and psychiatric disorders and cognitive dysfunction. This has mainly been demonstrated using genetically modified animal models and neuropharmacological analyses. The regulatory mechanisms of IEG expression have been investigated recently and have re-emphasized the role of IEG expression in plasticity-related processes as well as elucidating molecular mechanisms and drug targets for neurological and psychiatric disorders. This review summarizes recent studies of IEG regulation, including our findings of IEG expression regulated by excitatory and modulatory neurotransmissions. In addition, we propose possible roles for IEG regulation in neurological and psychiatric disorders and long-lasting neural functions. This review improves our understanding of the association between IEG regulation and neural function and diseases, and may promote the discovery of novel drug targets for psychiatric disorders.