After repeated exposures, many individuals develop tolerance to the adverse health effects of inhaled pollutants. Pulmonary tolerance can be characterized as the ability of the lung to withstand the adverse actions of a toxic compound after repeated exposures. To determine whether genetic background is important to the development of pulmonary tolerance to inhaled pollutants, 11 inbred strains of mice were exposed once (1×) or for 5 consecutive days (5×) to 1.0 mg/m³ of zinc oxide (ZnO). Development of pulmonary tolerance was assessed by measuring polymorphonuclear leukocyte and protein levels in bronchoalveolar lavage fluid and comparing the responses of the 1× and 5× groups. Significant interstrain variation in polymorphonuclear leukocyte and protein responses was observed between the groups with 1× and 5× exposures, which indicates that genetic background has an important role in the development of pulmonary tolerance. The BALB/cByJ strain and the DBA/2J strain were the most tolerant and nontolerant, respectively. The CByD2F1/J offspring were uniformly nontolerant. The development of tolerance was also investigated in BALB/cByJ and DBA/2J mice after 1× and 5× exposure to ozone and aerosolized endotoxin. Discordance in the phenotypic pattern of pulmonary tolerance among strains after exposure to ZnO, ozone, and endotoxin suggested that different mechanisms may be responsible for the development of pulmonary tolerance to these agents.