Extramammary Paget’s disease (EMPD) is a rare malignant adenocarcinoma with a poor prognosis when invasive or metastatic, and no standardized care when inoperable. One-third of EMPDs overexpress HER2/ERBB2 (human epidermal growth factor receptor 2), highlighting the potential efficacy of HER2 inhibitors in EMPD. Including an institutional case, we reviewed 70 previously published cases treated with at least one HER2 inhibitor for a metastatic or locally advanced EMPD (representing a total of 92 therapeutic lines), retrieved from PubMed and Scopus, to assess their efficacy, tolerability, and prescribing procedures. Monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates have been reported, with trastuzumab being the most used. In our study, HER2 inhibitors demonstrated a median progression free survival (PFS) of 12.5 months when used as first-line therapy (12 months when used as monotherapy, and 13.3 months when combined with another systemic treatment – mostly chemotherapeutic agents). The search for HER2 overexpression (through immunohistochemistry and fluorescence in situ hybridization/FISH) may be proposed in all cases of advanced EMPD, ideally in both the primary and metastatic sites, with testing for ERBB2 mutations, particularly in cases without HER2 overexpression. For patients in good general condition, a combination of a HER2 inhibitor and chemotherapy may be proposed, but good responses have also been observed with HER2 inhibitors as monotherapy, which shows excellent tolerability. Numerous types of HER2 inhibitors are now available, using different mechanisms of action, and may be effective even after progression on a first-line HER2 inhibitor.