Neurons communicate with one another at specialized contact sites called synapses, composed of pre- and postsynaptic compartments. Presynaptic compartments, or ‘boutons', signal to the postsynaptic compartment by releasing chemical neurotransmitter in response to incoming electrical impulses. Recent studies link defects in the function of presynaptic boutons to the etiology of several neurodevelopmental and neurodegenerative diseases, including autism, schizophrenia and Alzheimer's disease. In this review, we describe five core functions of presynaptic boutons and the molecules that mediate these functions, focusing on a subset that are linked to human disease. We also discuss potential mechanisms through which the loss or alteration of these specific molecules could lead to defects in synaptic communication, neural circuit function and, ultimately, cognition and behavior.