The H3 histamine receptor is expressed in many brain regions, including those involved in sleep/wake regulation and cognitive functions. Inhibition of the H3 receptor leads to increased release of multiple neurotransmitters in these regions, making this receptor an ideal target for the potential enhancement of arousal and/or cognitive processes. The high interest level by several pharmaceutical companies in H3 receptors as potential drug targets has produced rapid advancement in novel compound series with different properties, providing a variety of preclinical tools as well as advancing several candidates into clinical trials. Multiple chemotypes have demonstrated efficacy in preclinical models covering a range of cognitive deficits, suggesting the potential value of H3 antagonists as cognition enhancers in a variety of disease states. These studies have revealed the actions of this class of compounds at the cellular, neuronal systems and behavioral levels. Recently, compounds with improved selectivity, pharmacokinetics and preclinical safety profiles have advanced into clinical trials for a number of potential indications. The results of these clinical trials are eagerly awaited and will increase our understanding of the properties of H3 receptor antagonists that will provide therapeutic value.