Generalized pustular psoriasis of Zambusch is a unique and challenging skin condition to successfully manage. Patients often encounter potentially high recurrence rates of pustular eruptions despite multidrug treatment regimens with high morbidity as a consequence. We report a case of generalized pustular psoriasis of Zambusch in a patient whose disease initially flared following early treatment with the anti-tumor necrosis factor alpha (anti-TNF-alpha) inhibitor etanercept but was later successfully managed with cyclosporine and reintroduction of etanercept. We also discuss therapeutic management options for generalized pustular psoriasis.