We have discovered that human vitiligo patients treated with narrow‐band UVB (NBUVB) demonstrated localized resistance to repigmentation in skin sites characterized by distinct cellular and molecular pathways. Using immunostaining studies, discovery‐stage RNA‐Seq analysis, and confirmatory in situ hybridization, we analyzed paired biopsies collected from vitiligo lesions that did not repigment after 6 months of NBUVB treatment (non‐responding) and compared them with repigmented (responding) lesions from the same patient. Non‐responding lesions exhibited acanthotic epidermis, had low number of total, proliferative, and differentiated melanocyte (MC) populations, and increased number of senescent keratinocytes (KCs) and of cytotoxic CD8+ T cells as compared with responding lesions. The abnormal response in the non‐responding lesions was driven by a dysregulated cAMP pathway and of upstream activator PDE4B, and of WNT/β‐catenin repigmentation pathway. Vitiligo‐responding lesions expressed high levels of WNT10B ligand, a molecule that may prevent epidermal senescence induced by NBUVB, and that in cultured melanoblasts prevented the pro‐melanogenic effect of α‐MSH. Understanding the pathways that govern lack of NBUVB‐induced vitiligo repigmentation has a great promise in guiding the development of new therapeutic strategies for vitiligo.