The diverse functions of histamine are mediated by four specific histamine receptor subtypes, which belong to the family of G-protein-coupled receptors. Here, we summarize data obtained with histamine-deficient L-histidine decarboxylase knockout and histamine receptor subtype knockout mice in inflammation models. Advantages and disadvantages of the knockout approaches compared with pharmacologic approaches are discussed critically. Due to many controversial data it is very difficult to draw clear-cut conclusions from the data provided in the literature. Thus, the published studies highlight the complexity of histamine function in inflammation and the need for much more systematic experimental work.