The functional roles of the medullary raphé, and specifically 5-HT neurons, are not well understood. It has previously been stated that the role of 5-HT has been so difficult to understand, because "it is implicated in virtually everything, but responsible for nothing"(Cowen PJ. Foreword. In: Serotonin and Sleep: Molecular, Functional and Clinical Aspects, edited by Monti JM, Prandi-Perumal SR, Jacobs BL, Nutt DJ. Switzerland: Birkhauser, 2008). Are 5-HT neurons important, and can we assign a general, or even specific, function to them given their diffuse projections? Recent data obtained from transgenic animals and other model systems indicate that the 5-HT system is not expendable, particularly during postnatal development, and likely plays specific roles in vital functions such as respiratory and thermoregulatory control. We recently provided a detailed and updated review of one specific function of 5-HT neurons, as central respiratory chemoreceptors contributing to the brain's ability to detect changes in pH/CO2 and stimulate adjustments to ventilation accordingly (9). Here, we turn our focus to recent data demonstrating that 5-HT neurons provide an essential excitatory drive to the respiratory network. We then further discuss their role in the CO2 chemoreflex, as well as other homeostatic functions that are closely related to ventilatory control. Last, we provide additional hypotheses/concepts that are worthy of further study, and how 5-HT neurons may be involved in human disease.