A specific serotonin receptor (Se-5HTR) has been identified in the beet armyworm, Spodoptera exigua and classified into 5-HT7 type. Se-5HTR expression was up-regulated in hemocytes and fat body in response to immune challenge. As being a GPCR, this receptor is presumably coupled with intracellular trimeric Gαs protein activating cAMP-dependent protein kinase (PKA) pathway to regulate several cellular functions. RNA interference (RNAi) of Se-5HTR as well as its downstream signal proteins exhibited significant suppression in cellular immune responses including nodulation and phagocytosis. Application of inhibitors to the signaling cascade suppressed the immune responses as well. To validate the Se-5HTR involvement in mediating cellular immunity, 5-HTR knock-out mutants were developed using CRISPR-Cas9 technique and suffered significant developmental anomalies.