Monoaminergic neurons located in the central nervous system (CNS) are organized into complex circuits which include noradrenergic (NA), adrenergic (Ad), dopaminergic (DA), serotonergic (5-HT), histaminergic (H), GABA-ergic and glutamatergic systems. Most of these circuits are composed of more than one and often several types of the above neurons. Such physiologically flexible circuits respond appropriately to both external and internal stimuli which, if not modulated adequately, can trigger pathophysiologic responses. A great deal of research has been devoted to mapping the multiple functions of the CNS circuitry, thereby forming the basis for effective neuropharmacological therapeutic approaches. Such lineal strategies that seek to normalize complex and mixed physiological disorders, however, meet only partial therapeutic success and are often followed by undesirable side effects and/or total failure. In light of these, we have worked to develop possible models of CNS circuitry that are less affected by physiological interaction using the models to design more effective therapeutic approaches. In the present review, we cite and present evidence supporting the dorsal raphe versus median raphe serotonergic circuitry as one model of a reliable paradigm, necessary to the clear understanding and therapy of many psychiatric and even non-psychiatric disturbances.