© 2016 Troy et al. Background: Asthma is strongly associated with allergic sensitization, but the mechanisms that determine why only a subset of atopics develop asthma are not well understood. The aim of this study was to test the hypothesis that variations in allergen-driven CD4 T cell responses are associated with susceptibility to expression of asthma symptoms. Methods: The study population consisted of house dust mite (HDM) sensitized atopics with current asthma (n = 22), HDM-sensitized atopics without current asthma (n = 26), and HDM-nonsensitized controls (n = 24). Peripheral blood mononuclear cells from these groups were cultured in the presence or absence of HDM extract for 24 h. CD4 T cells were then isolated by immunomagnetic separation, and gene expression patterns were profiled on microarrays. Results: Differential network analysis of HDM-induced CD4 T cell responses in sensitized atopics with or without asthma unveiled a cohort of asthma-associated genes that escaped detection by more conventional data analysis techniques. These asthma-associated genes were enriched for targets of STAT6 signaling, and they were nested within a larger coexpression module comprising 406 genes. Upstream regulator analysis suggested that this module was driven primarily by IL-2, IL-4, and TNF signaling; reconstruction of the wiring diagram of the module revealed a series of hub genes involved in inflammation (IL-1B, NFkB, STAT1, STAT3), apoptosis (BCL2, MYC), and regulatory T cells (IL-2Ra, FoxP3). Finally, we identified several negative regulators of asthmatic CD4 T cell responses to allergens (e.g. IL-10, type I interferons, microRNAs, drugs, metabolites), and these represent logical candidates for therapeutic intervention. Conclusion: Differential network analysis of allergen-induced CD4 T cell responses can unmask covert disease-associated genes and pin point novel therapeutic targets.