Abstract: FE65, initially identified as a binding partner of amyloid precursor protein (APP), is an adaptor protein enriched in the brain and regulated during development. FE65 belongs to the FE65 protein family. This family is comprised of three members, FE65, FE65 like-1 (FE65L1), and FE65 like-2 (FE65L2). The three members share a conserved structure: a tryptophan-tryptophan (WW) domain and two successive phosphotyrosine-binding (PTB) domains. Despite being structurally similar, the three proteins differ in their expression patterns. FE65 is brain-enriched while FE65L1 and FE65L2 are more ubiquitously expressed. Therefore, FE65 has drawn more research interest than the other two homologs. Insights into the potential functions of the FE65 family have been obtained through studies on its interaction partners. Recently, emerging evidence suggests multiple roles of FE65 and its interactors during neuronal developmental processes including neurogenesis, neuronal migration and positioning, neurite outgrowth, and synaptic plasticity (Figure 1).