Specific immunotherapy is a very effective and well-tolerated therapeutic option in patients with Hymenoptera venom allergy. Many patients can be successfully treated, and severe side-effects are rarely seen. In most cases local swelling of the injection site is noticed, whereas systemic reactions are uncommon. No reliable biomarkers to prove the positive response to the specific immunotherapy have been validated. But on the other hand the failure of the venom immunotherapy can be verified by performing a sting challenge test; in this case the maintenance dose of the venom immunotherapy has to be increased and the sting challenge test has to be repeated. This approach works well most of the patients. In rare cases severe anaphylactic reactions occur during the initiation of the venom immunotherapy due to individual risk factors. While in the past this necessitated discontinuation of the specific immunotherapy, the current situation has remarkably changed. Since the IgE-antibody omalizumab has been licensed for different indications, a new therapeutic option is available. We have employed this approach since 2005. We share our own practical experience as well as recent data, presenting a management approach for Hymenoptera venom allergy in high-risk patients.