Anatomical and functional evidence suggests that the PFC is fairly unique among all cortical regions, as it not only receives input from, but also robustly projects back to mesopontine monoaminergic and cholinergic cell groups. Thus the PFC is in a position to exert a powerful top-down control over several state setting modulatory transmitter systems that are critically involved in the domains of arousal, motivation, reward/aversion, working memory, mood regulation, and stress processing. Regarding this scenario, the origin of cortical afferents to the ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDTg), and median raphe nucleus (MnR) was here compared, by using the retrograde tracer cholera toxin subunit b (CTb). CTb injections into VTA, LDTg, or MnR produced retrograde labeling in the cortical mantle, which was mostly confined to medial, orbital, and lateral PFC subdivisions, along with rostral and mid-cingulate areas. Remarkably, in all of the three groups, retrograde labeling was densest in layer V pyramidal neurons of the infralimbic, prelimbic, medial orbital and frontal polar cortex. Moreover, a conspicuous lambda-shaped region around the apex of the rostral pole of the nucleus accumbens stood consistently out as heavily labeled. At almost all rostrocaudal levels through the PFC analyzed, retrograde labeling was strongest following injections into MnR and weakest following injections into VTA. Altogether, our findings reveal a broadly similar set of prefrontal afferents to VTA, LDTg, and MnR, further supporting an eminent functional role of the PFC as a controller of all major state setting mesopontine modulatory transmitter systems.