Breast cancer is the second most common cancer worldwide, and the leading cause of cancer death in women. Several studies underlined the critical role of histamine in breast cancer development and progression. This review addresses the latest evidence regarding the involvement of histamine and histamine receptors in breast cancer, focusing particularly in the histamine H₄ receptor (H₄R). Histamine concentration in breast cancer tissues was found to be higher than that in normal tissues of healthy controls by means of an increase in the activity of histidine decarboxylase (HDC), the enzyme involved in histamine production. The expression of H₄R in different experimental models and human biopsies, the associated biological responses, as well as the in vivo treatment of experimental tumors with H₄R ligands is reviewed. Evidence demonstrates that the H₄R exhibits a key role in histamine-mediated biological processes such as cell proliferation, senescence and apoptosis in breast cancer. The polymorphisms of the H₄R and HDC genes and their association with breast cancer risk and malignancy reinforce the critical (patho)physiological role of H₄R in breast cancer. In addition, H₄R agonists display anti-tumor effects in vivo in a triple negative breast cancer model. The findings support the exploitation of the H₄R as a molecular target for breast cancer drug development.