Histamine is a biogenic amine with extensive effects on many cell types, including important immunologic cells, such as antigen-presenting cells, natural killer cells, epithelial cells, and T and B lymphocytes. Histamine and its 4 receptors represent a complex system of immunoregulation with distinct effects dependent on receptor subtypes and their differential expression. These are influenced by the stage of cell differentiation, as well as microenvironmental influences, leading to the selective recruitment of effector cells into tissue sites accompanied by effects on cellular maturation, activation, polarization, and effector functions, which lead to tolerogenic or proinflammatory responses. In this review we discuss the regulation of histamine secretion, receptor expression, and differential activation of cells within both the innate and adaptive immune responses. It is clear that the effects of histamine on immune homeostasis are dependent on the expression and activity of the 4 currently known histamine receptors, and we also recognize that 100 years after the original identification of this biogenic amine, we still do not fully understand the complex regulatory interactions between histamine and the host immune response to everyday microbial and environmental challenges.