In the present review, we will discuss the recent advances in the understanding of the role of histamine and histamine receptors in cancer biology. The controversial role of the histaminergic system in different neoplasias including gastric, colorectal, oesophageal, oral, pancreatic, liver, lung, skin, blood and breast cancers will be reviewed. The expression of histamine receptor subtypes, with special emphasis on the histamine H 4 receptor, in different cell lines and human tumours, the signal transduction pathways and the associated biological responses as well as the in vivo treatment of experimental tumours with pharmacological ligands will be described. The presented evidence demonstrates that histamine regulates cancer‐associated biological processes during cancer development in multiple cell types, including neoplastic cells and cells in the tumour micro‐environment. The outcome will depend on tumour cell type, the level of expression of histamine receptors, signal transduction associated with these receptors, tumour micro‐environment and histamine metabolism, reinforcing the complexity of cancer disease. Findings show the pivotal role of H 4 receptors in the development and progression of many types of cancers, and considering its immunomodulatory properties, the H 4 receptor appears to be the most promising molecular therapeutic target for cancer treatment within the histamine receptor family. Furthermore, the H 4 receptor is differentially expressed in tumours compared with normal tissues, and in most cancer types in which data are available, H 4 receptor expression is associated with clinicopathological characteristics, suggesting that H 4 receptors might represent a novel cancer biomarker.