Abstract Asthma is a highly prevalent and heterogeneous disease characterized by airway hyperreactivity (AHR) and an influx of immune cells including eosinophils and neutrophils in the bronchoalveolar lavage (BAL). Furthermore, there are patient subsets, such as severe asthmatics, who are unresponsive to corticosteroids or bronchodilators. Research efforts targeting these cohorts of asthma patients however are severely lacking due to an inadequacy in relevant biological mouse models. For the first time, we immunophenotyped 150+ inbred and RI mouse strains in the Hybrid Mouse Diversity Panel (HMDP) under steady state conditions and after house dust mite (HDM) challenge to assess the lung function, BAL cell composition, serum immunoglobulin levels, as well as quantification of lung and peripheral immune cells. These results revealed at least three unique groups of strains that, when exposed to the same allergen, respond with three distinct systemic and local phenotypes of lung inflammation, specifically a high Th-2 response, a low Th-2 response, and neutrophilia. These murine models of AHR mirror human cohorts of asthma previously underrepresented in ongoing research efforts. We are currently designing mechanistic studies focusing on identifying the genetic factors responsible for these distinct phenotypes. The results of these combined studies may lead to a better understanding of asthma heterogeneity and provide a foundation for further elucidation of the pathogenetic mechanisms of each phenotype of asthma utilizing relevant animal models.