Several investigations reported modulation of lymphocyte functions following activation of the histamine H2 receptor. However, few data have accumulated with regard to the distribution of histamine H2 receptors on different lymphocyte subsets. Conversely, the distribution of histamine H1 receptors on different lymphocyte subsets has been thoroughly analyzed using specific radioligands, whereas the functional significance of histamine H1 receptor ligation on lymphocytes has not been fully elucidated yet. Recent investigations suggest that H1R signaling on lymphocytes may enhance whereas activation of the H2R may inhibit lymphocyte responses. In this review, the authors discuss the current knowledge on distribution and functional significance of histamine H1 and histamine H2 receptors on human lymphocytes.