Histamine is a pleiotropic mediator involved in a broad spectrum of (patho)-physiological processes, one of which is the regulation of inflammation. Compounds acting on three out of the four known histamine receptors are approved for clinical use. These approved compounds comprise histamine H1-receptor (HR) antagonists, which are used to control allergic inflammation, antagonists at HR, which therapeutically decrease gastric acid release, and an antagonist at HR, which is indicated to treat narcolepsy. Ligands at HR are still being tested pre-clinically and in clinical trials of inflammatory diseases, including rheumatoid arthritis, asthma, dermatitis, and psoriasis. These trials, however, documented only moderate beneficial effects of HR ligands so far. Nevertheless, pre-clinically, HR still is subject of ongoing research, analyzing various inflammatory, allergic, and autoimmune diseases. During inflammatory reactions in gut tissues, histamine concentrations rise in affected areas, indicating its possible biological effect. Indeed, in histamine-deficient mice experimentally induced inflammation of the gut is reduced in comparison to that in histamine-competent mice. However, antagonists at HR, HR, and HR do not provide an effect on inflammation, supporting the idea that HR is responsible for the histamine effects. In the present review, we discuss the involvement of histamine and HR in inflammatory and inflammation-associated diseases of the gut.