Histamine influences many cell types involved in the regulation of innate and adaptive immune responses including antigen-presenting cells (APCs), Natural Killer (NK) cells, epithelial cells, T lymphocytes and B lymphocytes. These cells express histamine receptors (HRs) and also secrete histamine, which can selectively recruit the major effector cells into tissue sites and affect their maturation, activation, polarization and effector functions leading to tolerogenic or pro-inflammatory responses. Histamine and its four receptors represent a complex system of immunoregulation with distinct effects of receptor subtypes and their differential expression, which changes according to the stage of cell differentiation as well as micro-environmental influences. In this review, we discuss histamine receptor expression and differential activation of cells within both the innate and adaptive immune response and the signal transduction mechanisms which influence their activity.