Allergic inflammation is a result of damaging immune responses stimulated by innocuous proteins and is mediated by a complex interplay between inflammatory cells including eosinophils, basophils, neutrophils, mast cells, dendritic cells and lymphocytes. The anatomic location of allergic inflammation determines the structural cells that become targets, such as airway smooth muscle cells, mucous secreting cells, keratinocytes, and other epithelial cells. The cytokine IL-4 is critical for this process and promotes activation of the transcription factor STAT6 and transcriptional co-factors that regulate pro-allergic gene expression. STAT6 is required for IL-4 mediated responses, Th2 cell differentiation and class switching to IgE and has been implicated in the progression of asthma, atopic dermatitis (AD), and eosinophilic esophagitis (EoE). STAT6 interacts with the co-factor Poly-ADP ribose polymerse-14 (PARP 14 or ARTD8), one of 17 PARPs with ADP-ribosyl transferase activity. PARP14 was initially identified as a transcriptional co-activator for STAT6, and PARP14 and the enzymatic activity associated with it promote Th2 cell differentiation. Allergic airway disease is attenuated in Parp14-/- mice or in mice treated with PARP inhibitor, PJ34. To study the role of PARP14 in EoE, we examined esophageal biopsies from children and demonstrated a correlation between the expression of eosinophilic chemo-attractant, CCL26 and PARP14. To study allergic skin inflammation, we used a mouse model of spontaneous inflammation (Stat6VT mice). We generated Stat6VTxParp14-/- mice and observed that Stat6VTxParp14-/- mice develop more severe AD-like lesions with increased morbidity compared to Stat6VT mice. However, PARP14 is not required in keratinocytes to mediate the expression of IL4 and Stat6 responsive genes important for skin barrier function, suggesting that PARP14 contributes to a hematopoietic cell-intrinsic function. Thus, the data suggests that PARP14 serves specific roles in allergic disease that vary with the target organ.