The prevalence of allergic diseases has increased rapidly in recent years. It is well established that the deleterious allergic response is initiated by T-cell recognition of major histocompatibility class II-peptide complexes at the surface of antigen-presenting cells. While this first signal gives antigen specificity to the adaptive immune response, a second nonspecific costimulatory signal is required by T cells to become fully activated. This signal is provided by interactions between antigen-presenting cells and T cells through molecules borne at the surfaces of the two cell types. Depending on the type of molecules involved, this secondary signal can promote the development of an inflammatory allergic reaction or may favor immune regulation. Several molecules of the B7 family (CD80, CD86, PD-1, ICOS, CTLA-4) and tumor necrosis factor receptor family (OX40, CD30, 4-1BB, Fas, CD27, CD40) play an important role in delivering costimulatory signals in early and late phases of allergic response. Therefore, costimulatory molecules involved in promotion or prevention of allergic immune responses are potential targets for the development of novel therapeutic approaches. This review aims to recapitulate our current understanding of the relationship between allergic diseases and costimulatory molecules.