The identification of histamine H3 (H3R) and H4 (H4R) receptors some years ago revived interest in histamine research and exposed attractive perspectives for the potential therapeutic exploitation of these new drug targets. While the H3R is mainly localised in the CNS, the H4R is primarily expressed in hematopoietic cells, indicating their function in neurotransmission and immunomodulation, respectively. Although structural similarities between H3R and H4R and species differences in their pharmacological profiles are causes of limitations in the evaluation of their biological profile, the development of selective ligands for these receptors facilitates the elucidation of their physiological and pathophysiological functions. The H3R is a recognised drug target for neuronal diseases, such as cognitive impairment, schizophrenia, sleep/wake disorders, epilepsy and neuropathic pain; a small number of selective H3R antagonists have already passed some clinical Phase II trials. The H4R is the newest identified member of the histamine receptor family. Preclinical data strongly suggest its potential therapeutic exploitation in allergy, inflammation, autoimmune disorders and possibly cancer. Considering the topicality of this area of research, this review focuses on the pharmacology of selected promising indications and the rationales for the application of H3R and H4R ligands.