A review of the anatomic organization of ascending serotonin projections is followed by recent findings showing that these axonal projections are not diffuse but have an intricate and orderly pattern. The dorsal and median raphe nuclei and the B9 cell group have overlapping but differential projections to all parts of the forebrain. While most raphe projections extensively overlap, the dorsal raphe projects most heavily to frontal cortex and striatum, while the median raphe predominantly innervates hippocampus and septum. Small clusters of raphe cells project in a mosaic pattern to multiple, widely distributed islands of cortex. Yet, a coarse topographic order is preserved in the ascending dorsal raphe projections. Recent studies demonstrate two classes of serotonin axon terminals that differ in axon morphology, cells of origin, regional distribution, and response to psychotropic drugs. Dorsal raphe axons are extremely fine and highly vulnerable to certain neurotoxic amphetamines, e.g., 3,4-methylenedioxymethamphetamine; median raphe axons have large varicosities and are resistant to these mood-elevating drugs. We propose that there are two anatomically and functionally distinct serotonergic projections to cortex and that neurons in the dorsal raphe nucleus appear to play a major role in the control of affective state.