Nectin-4 is a transmembrane receptor that is implicated in migration, adhesion, and proliferation of tumor cells. It has minimal expression in healthy adult tissue but is overexpressed in a number of cancers, with higher expression levels seen in breast, bladder, colorectal, gallbladder, gastric, and non-small cell lung cancers. Enfortumab vedotin is an antibody-drug conjugate against nectin-4 that has been studied in a number of solid tumors and is FDA-approved for advanced urothelial cancers (including in combination with pembrolizumab). There are a number of other nectin-4-targeting agents under investigation. This review summarizes nectin-4 expression (membranous and cytoplasmic)/amplification in cancer and its potential as a response biomarker, as well as clinical trials of enfortumab vedotin and novel nectin-4 targeting agents. Biomarker-driven approaches merit investigation for nectin-4 directed across tumor types.