Background: Tree nut allergy is usually life-long and potentially life-threatening. Standard of care consists of strict avoidance of the culprit nut and symptomatic treatment of accidental reactions. Objective: To evaluate the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing on, but not limited to, immunotherapy. Methods: We systematically searched three bibliographic databases for studies published until July 2022 for active treatments of IgE-mediated allergy to tree nuts (walnut, hazelnut, pistachio, cashew, and almond) with allergen-specific immunotherapy (AIT) using oral (OIT), sublingual (SLIT), epicutaneous (EPIT) or subcutaneous (SCIT) delivery, or with other disease-modifying treatments. Results: We included 17 studies (three randomized, double-blinded, placebo-controlled, five quasi-experimental prospective cohorts, five prospective cohorts, two retrospective cohorts, and two case reports. Three studies investigated sublingual immunotherapy, five investigated oral immunotherapy to a single tree nut, and six used multi-food oral immunotherapy with (four) or without (two) omalizumab. The remaining studies investigated the effectiveness of monoclonal antibodies in multi-food allergic patients, including patients with a tree nut allergy. The heterogeneity of the studies prevented pooling and meta-analysis. Conclusion: Even though strict avoidance remains the standard of care for patients with tree nut allergy, alternative approaches have been tested in clinical trials and real-life studies. These new concepts require further investigation with more well-designed studies including well-characterized nut allergic patients before implementing them in daily clinical practice.