Constitutive activity has been mainly recorded for numerous overexpressed and/or mutated receptors. The histamine H 3 receptor (H 3R) is a target of choice to study the physiological relevance of this process. In rodent brain, postsynaptic H 3Rs show high constitutive activity, and presynaptic H 3 autoreceptors that show constitutive activity have a predominant role in inhibiting the activity of histamine neurons. H 3R inverse agonists abrogate this constitutive brake and enhance histamine release in vivo. Some of these inverse agonists have entered clinical trials for the treatment of cognitive and food intake disorders. Studies performed in vitro and in vivo with proxyfan show that this H 3R ligand is a ‘protean agonist’ – that is, a ligand with a spectrum of activity ranging from full agonism to full inverse agonism depending on the level of H 3R constitutive activity. Consistent with its physiological and therapeutic relevance, the constitutive activity of H 3R thus has a major function in the brain and regulates the activity of H 3R-targeted drugs.