14-3-3s are a family of ubiquitously expressed adaptor proteins that regulate hundreds of functionally diverse ‘client proteins.’ In humans, there are seven isoforms with conserved structure and function. 14-3-3s typically bind to client proteins at phosphorylated serine/threonine motifs via a linear binding groove. Binding can have a variety of effects on the stability, activity and/or localization of the client protein. 14-3-3s are generating significant interest as potential drug targets for their involvement in cellular homeostasis and disease. They are especially abundant in the central nervous system (CNS) and are implicated in numerous CNS diseases, often through specific interactions with disease-relevant client proteins. Several tool compounds that can modulate 14-3-3 interactions with client proteins to elicit therapeutic effects have recently been described. Here we offer a perspective on the functions of 14-3-3s in neurons and the potential development of drugs to therapeutically target 14-3-3 PPIs for CNS diseases.