The serotonergic system of the central nervous system (CNS) has been implicated in a broad range of physiological functions and behaviors, such as cognition, mood, social interaction, sexual behavior, feeding behavior, sleep-wake cycle and thermoregulation. Serotonin (5-hydroxytryptamine, 5-HT) establishes a plethora of interactions with neurochemical systems in the CNS via its numerous 5-HT receptors and autoreceptors. The facets of this control are multiple if we consider the molecular actors playing a role in the autoregulation of 5-HT neuron activity including the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2B, 5-HT7 receptors as well as the serotonin transporter. Moreover, extrinsic loops involving other neurotransmitters giving the other 5-HT receptors the possibility to impact 5-HT neuron activity. Grasping the complexity of these interactions is essential for the development of a variety of therapeutic strategies for cognitive defects and mood disorders. Presently we can illustrate the plurality of the mechanisms and only conceive that these 5-HT controls are likely not uniform in terms of regional and neuronal distribution. Our understanding of the specific expression patterns of these receptors on specific circuits and neuronal populations are progressing and will expand our comprehension of the function and interaction of these receptors with other chemical systems. Thus, the development of new approaches profiling the expression of 5-HT receptors and autoreceptors should reveal additional facets of the 5-HT controls of neurochemical systems in the CNS.