The 5-HT2A receptor is an attractive GPCR target for treatment of various neurological disorders. 5-HT2A agonists are commonly used clinically for treatment, but are limited by undesirable effects mediated by increased serotonergic tone through both 5-HT2A and related 5-HT receptors. Positive allosteric modulators (PAMs) which do not directly activate the receptor, but increase the receptor's activity in response to the endogenous ligand may provide safer alternatives. Here, we describe the development of a FLIPR assay to assess PAM activity at the 5-HT2A receptor, and utilise this assay to screen a library of ~5,000 compounds. This screen identified 2 potential hits, demonstrating the difficulty in identifying PAMs for the 5-HT2A receptor.