The skin is directly in contact with environmental molecules which are present in the air or directly in contact with the epidermis. Despite the assumption that it has a barrier role which could prevent the penetration of molecules, the skin is permeable to all substances from the low molecular weight xenobiotics to the high molecular weight proteins. Only the degree of permeability varies depending on the physiological state of the skin and the chemical properties of molecules. Recent insights into the pathophysiology of allergic skin diseases have shown that allergen penetration is not the major factor in explaining why some patients become allergic while others maintain an immunological tolerance to the penetrating molecules. Indeed, the functional properties of some allergenic molecules able to induce activation of innate immunity appear to be far more important in the development of allergy than their ability to penetrate the skin easily.