Eosinophilic esophagitis (EoE) has become a common gastrointestinal disease. It is characterized by severe eosinophil infiltration in the esophagus. EoE is strongly associated with food allergy, asthma, atopic dermatitis, and other allergic diseases. T lymphocytes, especially Th2 cells, play an instrumental role in the development of allergic inflammation. Recent studies have shown that the ligation of co-stimulatory molecules contributes to the activation, differentiation, and proliferation of T cells. In this review, we will discuss the growing evidence of co-stimulatory molecules including OX40, Light, and HVEM in the pathogenesis of Th2-driven EoE. Our goal is to provide the rationale for the development of novel therapy therapies that target co-stimulatory molecules.