Abstract The present model of epinephrine containing and PNMT containing neurons in rat brain (and by extension other species) implies that epinephrine is primarily a postsynaptic metabolite of norepinephrine in forebrain due to the probable postsynaptic localization of PNMT. As a result the most physiologically relevant pool is found in extracellular space with the bulk of tissue epinephrine found co-stored in noradrenergic terminals. Changes in the extracellular pool of epinephrine are effected by changes in the extracellular norepinephrine concentration as in times of increased release, reuptake blockade or inhibition of degradation. α 2-Adrenergic receptors associated with cells not necessarily in synaptic contact with the noradrenergic terminal containing epinephrine could be stimulated through this extracellular pool. The majority of PNMT containing cells in the brainstem/medulla appear to also contain other catecholamine biosynthetic enzymes. The present model suggests that epinephrine formed in these neurons is primarily used as a co-transmitter with norepinephrine formed in these same terminals. The balance of norepinephrine to epinephrine found in vesicles in these terminals would be a function of intraneuronal PNMT activity, MAO activity and reuptake which would be the major regulator of intraneuronal norepinephrine concentrations. The literature is reviewed in these contexts, questioning the existence of classical epinephrine neurons. Evidence is presented in support of a model for postsynaptic synthesis of epinephrine in the forebrain, especially during times of high norepinephrine release. The classic model of compartmentalization of biosynthetic enzymes is used in support of a cotransmitter role of epinephrine in the brainstem/medulla. Epinephrine is considered a unique metabolite of norepinephrine with important pharmacological actions and a receptor subtype in brain which monitors and regulates its formation. Epinephrine is recognized by the uptake system on noradrenergic terminals and vesicles and can therefore compete for storage in these noradrenergic neurons. Based on the distribution of PNMT and its association with major noradrenergic fiber tracts, epinephrine can be considered a site-selective metabolite of physiological and neuronal importance. Due to the compartmentalization of synthetic enzymes, it is probably not a classical neurotransmitter in the central nervous system, although it may be the primary catecholamine neurotransmitter in some medullary neurons.