VPS10P-domain receptors, such as SORLA and sortilin, constitute a recently identified class of type-1 receptors that are expressed in neurons. Family members are multifunctional proteins that target a range of ligands, including trophic factors and neuropeptides but also other transmembrane proteins. New findings have revealed unexpected roles for VPS10P-domain receptors as regulators of neuronal viability and function through the regulation of both protein transport and signal transduction. Loss of these activities might contribute to the pathophysiology of devastating disorders of the nervous system, including Alzheimer's disease, affective disorders and post-traumatic neuronal cell death.