This chapter provides a review of basic research as well as clinical literature in support of the idea that altered serotonergic homeostasis is prominently involved in the pathogenesis of Autism Spectrum Disorder (ASD). Animal models of cortical serotonergic effects in development and plasticity are reviewed and juxtaposed to neuropathological and clinical findings in ASD. Based on the emerging conceptualization of ASD as a developmental disorder of cortical connectivity, we present a hypothesis about the role of serotonin in altered cortical network formation, as a substrate for altered cognitive function. Investigations into the role of serotonin in immune regulation, and particularly neuroimmune regulation, support a role for serotonin in a variety of homeostatic functions that may be impaired in ASD and can contribute to altered brain development and function. A unified hypothesis such as proposed here could provide an avenue towards early identification of biomarkers as well as therapeutic strategies. We hope to provide an impetus for new investigations into a ‘serotonergic hypothesis’ for ASD.