Sortilin is a type-1 receptor expressed in neurons of the central and peripheral nervous systems. Initially considered a rather peculiar receptor resembling an intracellular sorting protein in yeast, sortilin has emerged as a key player in the regulation of neuronal viability and function. It acts as a receptor of neurotrophic factors and neuropeptides, but also as a co-receptor to cytokine receptors, tyrosine receptor kinases, G-protein coupled receptors and ion-channels. Here, we review recent findings that identified multiple roles for sortilin in the cellular transport and signaling. Furthermore, we discuss how sortilin contributes not only to the functional integrity of the nervous system during physiological conditions but also plays an important role during neuronal injury and disease processes.