Nickel is the most common contact allergen. Nickel-containing orthodontic appliances are implicated in allergic reactions, which represent a type IV delayed hypersensitivity immune response. Nickel hypersensitivity is diagnosed through the patient’s history, clinical findings, and biocompatibility testing (patch skin tests). While testing the level of nickel in mucosa and blood does not have diagnostic value, the in vitro cell proliferation assays could be an important diagnostic tool. Allergic hypersensitivity reactions may involve intra- and extra-oral clinical signs, comprising diffuse erythema, edema, eczema, fissuring, desquamation, and symptoms such as itching and soreness. Caution and close monitoring should be exercised when placing nickel-containing orthodontic appliances in patients with known histories of nickel contact dermatitis, as the original treatment approach might need modification. The aim of this article is to provide orthodontists with the necessary knowledge about the biologic mechanisms, diagnostic tools, and clinical signs, as well as the treatment alternatives to nickel-induced allergic reactions. World J Orthod 2008; 9:399–406.