Although the histamine H(3) receptor was identified pharmacologically in 1983, and despite widespread pharmaceutical interest in the target, no compound interacting specifically with this site has undergone successful clinical examination to develop the necessary proof-of-concept data. Therefore, clinical knowledge of the therapeutic potential of H(3) receptor antagonists in neuropsychiatric diseases, in metabolic diseases or in sleep disorders has yet to determine if the preclinical data that show broad efficacy in animal models of the aforementioned states are relevant to current unmet medical needs. H(3) receptors are complex, with species-related sequence differences that impact pharmacological responses. The receptors have a complex gene organization that provides opportunity for multiple slice isoforms, most of which remain poorly characterized even within a species. H(3) receptors are constitutively active, although the extent of this could vary either between species and/or receptor splice isoforms, both of which may provide opportunity for preferential coupling to different G-proteins. Thus, it is not surprising that the pharmacological effects of known H(3) ligands are complex and diverse, since these agents may act both as agonists and antagonists in different systems. Moreover, other compounds show inverse agonism in some models but neutral antagonist activity in others. Some of this diversity may be related to different ligand-dependent receptor activation states or to the effects of key amino acids important for ligand recognition. This commentary provides an overview of these complexities as applied to the H(3) receptor and the challenges these intricacies create for drug discovery.