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Generalized pustular psoriasis (GPP) is a rare but serious and difficult to treat cutaneous disease, with high morbidity and mortality rates. Despite the numerous treatment regimens available, the overall quality of evidence-based research is limited with a lack of an algorithmic approach available. In this review, we aim to evaluate the current level of evidence regarding the efficacy and safety/tolerability of systemic monotherapies available in the treatment of GPP. A comprehensive MEDLINE, EMBASE, and PubMed search of clinical studies examining systemic monotherapy treatment options for GPP was conducted. In total, 31 studies met eligibility criteria. Described treatment modalities included retinoids, cyclosporine, biologics, and dapsone. Despite the lack of high-quality evidence or a well-accepted treatment algorithm for GPP, systemic retinoids, cyclosporine, biologics, and dapsone are all possible first-line agents, with retinoids being one of the best-supported treatment options and biologics as an emerging therapeutic field with great potential requiring additional data. However, the final choice of treatment should be considered within the unique context of each patient.