With the deepening research on pathogenesis of depression, the focus has diverted from the mechanism of regulating monoamines to the basic pathophysiology of depression and the long-term mechanism of antidepressant treatments. cAMP response element binding protein (CREB) in the brain, especially in the hippocampi, as a converging agent of many intracellular signaling transduction pathways is getting increasing attention. To better understand the basic pathophysiology of depression and the long-term mechanism of antidepressant treatments, it is significant to make clear the correlation between hippocampal CREB and antidepressant treatments. This review mainly refers to the formation of CREB and its distribution in hippocampi, the upstream signaling transduction pathways of hippocampal CREB and antidepressant treatments, and the possible antidepressant mechanisms by regulating hippocampal CREB.