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Understanding the phenotypic and transcriptional signature of immunoglobulin E (IgE)–producing cells is fundamental to plasma cell (PC) biology and development of therapeutic interventions for allergy. Here, using a mouse model of intranasal house dust mite (HDM) exposure, we showed that short-lived IgE PCs emerge in lung draining lymph nodes (dLNs) during early exposure (<3 weeks) and long-lived IgE PCs accumulate in the bone marrow (BM) with prolonged exposure (>7 weeks). IgE PCs had distinct surface and gene expression profiles in these different tissues compared with other Ig isotypes. IgE BMPCs up-regulated genes associated with prosurvival and BM homing, whereas IgE dLN PCs expressed genes associated with recent class switching and differentiation. IgE PCs also exhibited higher expression of endoplasmic reticulum (ER) stress and protein coding genes and higher antibody secretion rate when compared with IgG1. Overall, this study highlights the unique developmental path and transcriptional signature of short-lived and long-lived IgE PCs. Editor's summary: Immunoglobulin E (IgE)–mediated allergic diseases can be fatal, yet our understanding of IgE-producing plasma cells (PCs) is limited. Vecchione et al. used a transgenic mouse reporter strain to characterize IgE PCs during chronic house dust mite exposure. IgE PCs were transcriptionally and phenotypically unique compared with other immunoglobulin isotypes, with higher levels of endoplasmic reticulum stress and increased antibody production. Short-lived IgE PCs appeared early in the lung draining lymph nodes post–allergen exposure, whereas long-lived bone marrow (BM) IgE PCs were not detected until much later. IgE BMPCs from humans with allergy also had unique transcriptional signatures. These findings demonstrate that IgE PCs are developmentally, transcriptionally, and functionally unique. —Hannah Isles [ABSTRACT FROM AUTHOR]