As exemplified particularly with vasopressin and oxytocin, release of neuropeptides within the brain occurs from dendrites, somata, and axons of neurosecretory neurons; mechanisms include activation of intracellular Ca2+ stores, changed strength of synaptic input and altered interaction between transcription factors and gene promoters. Upon demand, both diffuse spread of neuropeptides in the extracellular fluid following dendritic release and focal release from axonal terminals may contribute to regionally and temporally varying combinations of neuromodulator and neurotransmitter actions, thus providing a theoretically unlimited variability in interneuronal signaling. Thus, instead of favoring volume or synaptic transmission following central neuropeptide release, a more dynamic concept is presented with multiple and variable modes of release and communication. This concept considers neuropeptides in the extracellular fluid of the brain rather than those in the cerebrospinal fluid or plasma as primary signals, triggering a variety of receptor-mediated effects, including those underlying behavioral and neuroendocrine regulation and psychopathology.