To evaluate the concept that genetic factors modulate susceptibility to agents that cause interstitial lung disease, animal models of interstitial lung disease caused by bleomycin or by inhalation of organic particulates (ovalbumin or bovine gamma globulin after specific immunization) were studied in strains of mice with different genetic backgrounds. Because immune processes have been implicated in modulating the susceptibility to agents that cause interstitial lung disease, we also compared congenic, resistant strains (strains with the same background but with different H-2 haplotypes) for their sensitivity to the same agents. In bleomycin-induced disease, the degree of lung disease was different in some of the different strains of mice and, in some strains, was related to H-2 locus genes since all strains with H-2^b haplotypes were high responders, whereas most of the strains with H-2^a, H-2^d, and H-2^k haplotypes were low responders. However, some of the strains of mice with the same H-2 haplotype but otherwise different genetic backgrounds had different responses to bleomycin, suggesting that there is also a role for non-H-2 genetic factors in modulating the response to this experimental interstitial lung disease. In the ovalbumin-induced lung disease model, as in bleomycin-induced lung disease, there were different strain susceptibilities: 2 of the 3 strains in the H-2^b group were high responders, as was 1 of the 3 strains in the H-2^k group. Interestingly, evaluation of the congenic, resistant strains showed that on the same backgrounds the H-2-related genes were able to modulate the degree of lung lesions, but on other genetic backgrounds the type of H-2 locus was irrevelant, suggesting that both H-2- and non-H-2-related genes could play a role in determining the severity of lung lesions in this model. Similarly, in the bovine gamma-globulin-induced lung disease, different strains showed different degrees of pulmonary derangement, depending on the H-2 loci but also on the background. Comparison of the results from all 3 agents showed that sensitivity of different strains of mice to the experimental interstitial lung disease induced by different agents was comparable and independent of the agent; for all 3 agents, susceptibility was related to both H-2 and non-H-2 genes. These data suggest that, at least in these murine models, the development of interstitial lung disease may be multifactorial, with a variety of immune- and non-immune-related genes contributing to the susceptibility to agents that cause interstitial lung disease.