Whereas some individuals develop immunity to bee sting and mount protective IgG4- mediated antibody responses to bee venom phospholipase A2 (PLA), others produce large amounts of PLA-specific IgE antibodies and become allergic to this, otherwise, innocuous antigen. PLA-specific IgE responses are the result of imbalanced T helper (Th)2-cell differentiation. There are multiple mechanisms driving the differentiation of naive CD4+ T cells into Th1- or Th2-cell phenotypes. Most of them are linked to the conditions occurring during initial or repeated encounters with the allergen, in the context of an antigen-presenting cell (APC). The different types of APC and their availability to display particular cytokine production profiles, pattern recognition receptors, costimulatory molecules and specific HLA haplotypes are key determinants for human Th1- and Th2-cell polarization.