Despite the overall excellent survival rates in patients affected by early cutaneous squamous cell carcinoma (CSCC), advanced forms of CSCC are associated with high patient mortality. To date, only limited therapeutic modalities have been implemented, including chemotherapy and radiotherapy. Systemic therapy was enriched by the addition of epidermal growth factor receptor inhibitors (EGFRi) in the last years. Unfortunately, the overall outcome of all these therapeutic strategies remains poor, therefore important unmet clinical needs persist. Thanks to a better understanding of the biology of advanced CSCC, new treatment options are now available. This article presents the current definition of advanced CSCC along with actual therapeutic options and discusses the strengths and limitations of a new promising systemic approach, which involves the use of immune checkpoint inhibitors.