The definition of the “atopic state”, i.e. subjects presenting at least one skin wheal with a minimum diameter of 3 mm induced by an allergen skin-prick test (ASPT), is based on the assumption that wheal size depends entirely on the amount of histamine produced in the antigen-antibody reaction. Several epidemiological studies have, however, demonstrated that an ASPT-elicited wheal is heavily modulated by “histamine skin reactivity” (HSR), i.e. the size of the wheal induced by a prick test performed with a given solution of histamine. HSR not only varies widely depending on the individual characteristics and geographical setting, but also changes over time; these differences in HSR markedly influence the amount of specific IgE required to produce a wheal of at least 3 mm in an ASPT. We should therefore ideally conceive the existence of two types of” atopic patients”: one type in whom “atopy” is mainly the result of an increased level of specific IgE antibodies, and another type in whom positive ASPTs are mainly the result of marked skin reactivity to even small amounts of histamine. If hyper-reactivity to histamine occurs not only in the skin but in parallel also in other parts of the organism, especially at the mucosal level, “normal” histamine production may cause chronic or recurrent clinical symptoms.