Nectin-4 is a tumor-associated antigen that is highly expressed on various cancer cells, and it has been further proposed to have roles in tumor development and propagation ranging from cellular proliferation to motility and invasion. Nectin-4 blockade reduces tumor proliferation and induces apoptosis in several malignancies. Nectin-4 has been used as a potential target in antibody-drug conjugate (ADC) development. Enfortumab vedotin, an ADC against Nectin-4, has demonstrated efficacy against solid tumor malignancies. Enfortumab vedotin has received US Food and Drug Administration approval for treating urothelial cancer. Furthermore, the efficacy of ADCs against Nectin-4 against solid tumors other than urothelial cancer has been demonstrated in preclinical studies, and clinical trials examining the effects of enfortumab vedotin are ongoing. Recently, Nectin-4 was reported to be highly expressed in several skin cancers, including malignant melanoma, cutaneous squamous cell carcinoma, and extramammary Paget's disease, and involved in tumor progression and survival in retrospective studies. Nectin-4-targeted therapies and ADCs against Nectin-4 could therefore be novel therapeutic options for skin cancers. This review highlights current knowledge on Nectin-4 in malignant tumors, the efficacy of enfortumab vedotin in clinical trials, and the prospects of Nectin-4-targeted agents against skin cancers.