Abstract Extensive preclinical research has been conducted in recent years to reveal the cell types, neuronal circuits and molecular and morphological changes implicated in the function of the dentate gyrus in depression. This was profoundly facilitated by the emergence of methods such as gene targeting, neuronal cell activity manipulation, including optogenetics and chemogenetics, and the development of novel RNA sequencing technology and powerful MRI imagers that were used in clinical studies. These advancements provided researchers with the precise skills needed to evaluate the changes in the dentate gyrus structure and cell function in rodent models as well as in brains of depressed and medicated patients. Here, we review these latest findings and discuss the existing gaps in our knowledge of the role of the dentate gyrus in depression and in mediating the response to antidepressant therapies.