It is generally accepted that seven-transmembrane receptors have the capacity to regulate cellular signaling systems in the absence of occupancy by a ligand (i.e. the receptors display constitutive activity). Drugs can increase (agonists), decrease (inverse agonists) or not change (antagonists) receptor activity towards a cellular effector. Moreover, some drugs (protean ligands) have multiple pharmacological properties (e.g. agonism towards one response and inverse agonism towards another response coupled to the same receptor and measured from the same cells, simultaneously). In this article, we describe response-dependent constitutive activity and ligand pharmacology for 5-HT2A and 5-HT2C receptors in vitro. Moreover, we provide evidence that 5-HT2A and 5-HT2C receptor constitutive activity is physiologically relevant in vivo and suggest that strong consideration should be given to the impact of constitutive receptor activity on disease and the therapeutic potential of inverse agonism.