Histamine is a bioactive amine which is considered a key player in the allergic response. Thus, histamine receptor blockers (antihistamines) play an important role in the treatment of a number atopic diseases such as allergic rhinitis, conjunctivitis, and acute and chronic forms of urticaria. Histamine is produced by immune cells but also by bacteria in the gut. Beyond its role in the acute allergic response, histamine exerts numerous effects by binding to its 4 pleiotropic G-protein coupled histamine receptors. Here, we describe the roles of these histamine receptors and antihistamines in the human system, clinical applications, side effects, and novel concepts for the usage of antihistamines with different specificity based on guidelines and recommendations. Statement of novelty: This review provides an overview of histamine receptors and links it to clinical relevance of antagonizing their action in clinical routine.