Second generation antipsychotics (SGAs), notably atypical antipsychotics includingolanzapine, clozapine and risperidone, can cause weight gain and obesity side ef-fects. Antagonism of serotonin 2c receptors (5-HT2cR) and activation of ghrelin re-ceptor type 1a (GHSR1a) signalling have been identified as a main cause of SGAinduced obesity. Here we review the pivotal regulatory role of the 5-HT2cR inghrelin-mediated appetite signalling. The 5-HT2cR dimerizes with GHSR1a to in-hibit orexigenic signalling, while 5-HT2cR antagonism reduces dimerization andincreases GHSR1a-induced food intake. Dimerization is specific to the unedited5-HT2cR isoform. 5-HT2cR antagonism by SGAs may disrupt the normal inhibi-tory tone on the GHSR1a, increasing orexigenic signalling. The 5-HT2cR and itsinteraction with the GHSR1a could serve as the basis for discovering novel ap-proaches to preventing and treating SGA-induced obesity.