Repeated inhalation of low levels of ovalbumin (OVA) by mice or rats preferentially induces tolerance in the IgE antibody class, and this process may represent an important protective mechanism that normally prevents allergic sensitization to air-borne antigens. Dose-response experiments involving exposure of a number of inbred rat strains to graded doses of aerosolized OVA confirmed the inverse relationship between sensitivity to tolerogenesis and IgE-responder phenotype. These experiments additionally demonstrated that F1 hybrids derived from low X high responder crosses co-inherited high sensitivity to tolerance induction, together with the low IgE-responder phenotype. Sensitivity to tolerance induction in low versus high IgE-responder strains was found to be independent of the route of administration of OVA, indicating that the relevant genetically determined control mechanism(s) operated systemically. However, pre-exposure of animals to a variety of exogenous agents, noteably inhaled irritants (NO2 and histamine), the inflammatory adjuvants pertussigen and aluminium hydroxide injected at sites that stimulate the regional lymph nodes draining the respiratory tract, or a single subcutaneous injection of the reticuloendothelial system stimulator oestradiol, were shown to partially abrogate this natural tolerance process and promote allergic sensitization.