Denervation of the hippocampus triggers reactive responses in neurons and glial cells in their affected strata in a temporally ordered fashion. Many of these responses have been studied extensively, focusing on the one hand on glial initiation and clearing responses during the degeneration phase and, on the other, on transneuronal reorganization and the newly adjusted physiological balance. We used the entorhinal cortex lesion (ECL) as a model system to study the cues that underlie the layer-specific sprouting response. This lesion destroys the perforant path, which is a massive excitatory projection to the dentate gyrus and hippocampus proper. In the deafferented zones of the hippocampus, sprouting of the remaining unlesioned fibers occurs, which replaces the lost afferences of the perforant path. We focus on candidate molecules which govern the layer-specific sprouting of the remaining axons and, in particular, on membrane-bound cues. The fact that layer-specific sprouting occurs even in the adult central nervous system (CNS) provides a valuable model for understanding the mechanisms of reactive neuronal growth and reorganization in the adult CNS. Isolation and analysis of the molecules involved in these mechanisms are important steps in understanding the potential and limitations of regeneration in the CNS.