Serotonin is one of the oldest neurotransmitters in evolutionary terms, and the serotonergic system is complex and multifaceted. Serotonin-producing neurons in the raphe nuclei provide serotonin innervations throughout various parts of the brain, modulating cellular excitability and network properties of targeted brain areas, and regulating mood, cognition and behavior. Dysfunctions of the serotonergic system are implicated in neuropsychiatric disorders including depression, schizophrenia, and drug abuse. Although the system has been studied for many years, an integrative account of its functions and computational principles remains elusive. This is partly attributed to the high variability and heterogeneity in terms of neuronal properties and receptor types, and its extensive connections with other brain regions. This Frontiers Research Topic e-book is a collection of recent experimental and computational work and approaches at multiple scales that provide the latest information regarding the integrated functions of the serotonergic system. The contributed papers include a variety of experimental and computational work, and human clinical studies.