Deafferentation of the dentate gyrus by unilateral entorhinal cortex lesion or unilateral perforant pathway transection is a classical model to study the response of the central nervous system (CNS) to denervation. This model has been extensively characterized in the rat to clarify mechanisms underlying denervation-induced gliosis, transneuronal degeneration of denervated neurons, and collateral sprouting of surviving axons. As a result, candidate molecules have been identified which could regulate these changes, but a causal link between these molecules and the postlesional changes has not yet been demonstrated. To this end, mutant mice are currently studied by many groups. A tacit assumption is that data from the rat can be generalized to the mouse, and fundamental species differences in hippocampal architecture and the fiber systems involved in sprouting are often ignored. In this review, we will (1) provide an overview of some of the basics and technical aspects of the entorhinal denervation model, (2) identify anatomical species differences between rats and mice and will point out their relevance for the axonal reorganization process, (3) describe glial and local inflammatory changes, (4) consider transneuronal changes of denervated dentate neurons and the potential role of reactive glia in this context, and (5) summarize the differences in the reorganization of the dentate gyrus between the two species. Finally, we will discuss the use of the entorhinal denervation model in mutant mice.