Immunoglobulin E (IgE) mediated immune responses seem to be directed against parasites and neoplasms, but are best known for their involvement in allergies. The IgE network is tightly controlled at different levels as outlined in this review. Genetic determinants were suspected to influence IgE regulation and IgE levels considerably for many years. Linkage and candidate gene studies suggested a number of loci and genes to correlate with total serum IgE levels, and recently genome-wide association studies (GWAS) provided the power to identify genetic determinants for total serum IgE levels: 1q23 (FCER1A), 5q31 (RAD50,IL13,IL4), 12q13 (STAT6), 6p21.3 (HLA-DRB1) and 16p12 (IL4R,IL21R). In this review, we analyse the potential role of these GWAS hits in the IgE network and suggest mechanisms of how genes and genetic variants in these loci may influence IgE regulation.