Histamine acts through four different receptors and ligands for two of these receptors have been used in clinical practice for many decades. Efficacy of drugs that target the histamine H1 receptor in allergic diseases such as urticaria, allergic rhinitis, and allergic conjunctivitis has provided a rationale for the association of histamine with allergy. However, these drugs are not efficacious in other diseases thought to be allergic in nature such as asthma and atopic dermatitis. Recent preclinical and clinical data have shown a role for histamine H4 receptor antagonists in these diseases. Histamine H4 receptor antagonists are efficacious in preclinical models of asthma, atopic dermatitis, and pruritus. Histamine H4 receptor antagonists have shown clinical efficacy in atopic dermatitis and asthma. Therefore, the histamine H4 receptor may play a role in diseases such as asthma and atopic dermatitis, which were long believed not to be mediated by histamine due to lack of efficacy of traditional antihistamines.