The adrenergic system is an important modulator of synaptic transmission in the central and peripheral nervous system. The endogenous catecholamines epinephrine and norepinephrine activate multiple G protein-coupled receptors (GPCR) to transmit their signal within the neurons. Previous studies highlighted the important role of the three subtypes of alpha(2)-adrenoceptors, alpha(2A), alpha(2B), alpha(2C), for neuronal function. However, the detailed knowledge about the brain regions, types of neurons and cells, subcellular localization, and intracellular signaling events has only been acquired recently. The present review summarizes recent insight derived from transgenic mouse models to distinguish alpha(2)-adrenoceptor functions mediated by the classical presynaptic alpha(2)-feedback autoreceptors in