Interleukin-23 (IL-23) inhibitors, including guselkumab, demonstrate high efficacy and a sustained clinical response in patients with moderate-to-severe psoriasis. However, in real-world clinical practice, patients often experience unplanned treatment interruptions due to medical, social, or logistical reasons. This review examines the causes of treatment discontinuation, its clinical consequences, and the prospects for remission recovery upon therapy reinitiation. Data from the VOYAGE 2 study and subsequent analyses have shown that discontinuation of IL-23 inhibitor therapy leads to a gradual loss of clinical effect, with the median time to PASI 90 loss ranging from 15 to 27 weeks. Nevertheless, reinitiation of guselkumab therapy restores a high level of clinical response in 80% or more of patients. Sustained remission after treatment interruption is associated with continued suppression of key cytokines along the IL-23/Th17 axis, including IL-17A, IL-17F, and IL-22. Despite the potential for regaining clinical effect, planned discontinuation of IL-23 inhibitors is not recommended due to the high risk of disease relapse and loss of disease control. However, the selective targeting of IL-23 enables modulation of pathogenic Th17 and Th22 cell populations, preserving the possibility of “resetting” the immune response after interruption. Unlike other therapeutic options, IL-23 inhibitors are less likely to deplete immunological memory and rarely result in a permanent loss of response. The accumulated evidence underscores the importance of an individualized treatment approach and the rational selection of therapeutic targets in the management of psoriasis.