Generalized pustular psoriasis (GPP) is a severe and rare form of psoriasis, being a potentially life-threatening condition, characterized by recurring episodes or flares of widespread cutaneous erythema with macroscopic sterile pustules. An irregular innate immune response is linked to GPP, which is considered an auto-inflammatory disorder, while innate and adaptive immunopathogenic responses are involved in psoriasis pathogenesis. In consequence, different cytokine cascades have been suggested to be mainly involved in the pathogenesis of each different psoriasis form, with the interleukin (IL)23/IL17 axis implied in plaque psoriasis, and the IL36 pathway in the GPP. As regards GPP treatment, conventional systemic drugs available for plaque psoriasis are usually used as the first-line treatment option. However, contraindications and adverse events often limit the use of these therapies. In this scenario, biologic drugs may represent a promising treatment option. To date, even if 12 different biologics have been approved for plaque psoriasis, none of these is approved for GPP where they are employed off-label. Recently, spesolimab, an anti-IL36 receptor monoclonal antibody, has been recently approved for GPP. The purpose of this article is to assess the current literature about the use of biological therapies for the treatment of GPP to establish the basis for a shared GPP management algorithm.