This systematic review evaluates the potential therapeutic options for desensitization of patients with IgE-mediated tree nut allergy, focusing, but not limited to, on immunotherapy. We 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. We included 26 studies, but the heterogeneity of the studies prevented pooling and meta-analysis. Immunotherapy with hazel pollen extracts might benefit patients with a secondary nut allergy due to cross-reactivity with PR-10 or profilin panallergens but is unlikely to be beneficial in patients with a severe nut allergy caused by seed storage proteins. Sublingual immunotherapy has a moderate efficacy but a favorable safety profile. Oral immunotherapy (OIT), single, or multi-nut, with or without omalizumab, is the most studied approach. In general, tree nut OIT is effective in conferring protection from accidental exposures, with safety similar to that demonstrated by peanut OIT. The observed cross-desensitization between tree nuts straightly affects the management options for multi-nut allergic patients.