Antihistaminic drugs have a rich history of clinical usage, especially in allergology, for alleviation of rash, itch, urticaria, edema, anaphylaxis and other conditions caused by histamine release in the presence of allergen. However, their action is not limited by the immune system, and also includes complex central nervous system (CNS) effects. Many of antihistaminic drugs are clinically used as anxiolytics, hypnotics and neuroleptics. However, they also have serous side-effects and may cause delirium - a serious condition presented as aroused, disorganized behavior often combined with hallucinations. Finally, antihistaminic agents are increasingly reported as drugs of abuse, often used recreationally, and leading to occasional toxic life-threatening effects and overdose. Here, we discuss chemical neuroscience of antihistaminic drugs in both human and animal (experimental) models, and outline their societal and mental health importance as commonly abused substances.