A potential limitation in the use of biologic drugs used to treat psoriasis is the development of anti-drug antibodies (ADAs). Many factors contribute to this unwanted immune response, from the product itself, to its mode of administration, the underlying disease, and patient characteristics. ADAs may decrease the efficacy of biologic drugs by neutralizing them or modifying their clearance and may account for hypersensitivity reactions. This article reviews the scientific basis of immunogenicity and the mechanisms by which it affects clinical outcomes. It also considers testing for immunogenicity and how biologic therapy of psoriasis may be tailored on the basis of immunogenicity.