Contrary to the impression that non-melanoma skin cancer is a banal and relatively trivial malignancy it causes about 1% of all cancer deaths. Cutaneous Squamous Cell carcinoma (CuSCC) make up a significant part of these deaths either from incurable loco-regional disease or metastatic disease. As is typical of the disease itself, these patients are often of advanced age, but the immunocompromised from organ transplantation or haematological malignancy are important populations. Systemic therapies have a long history in palliative therapy for CuSCC, but not a particularly extensively studied one. Cytotoxic chemotherapy is active with response rates derived from multiple small studies of 17-85%; as is often the case in solid tumour oncology responses are rarely durable. The Epidermal Growth Factor Receptor has been targeted with both small molecular inhibitors and monoclonal antibodies. Disease control rates of the order of 50-70% were seen but again durability remains an issue. Immunotherapy using interferon with retinoids also showed significant response rates in very small trials. The high rates of mutation seen in CuSCC and relationship with immunosuppression suggested that checkpoint inhibitors might be active. Checkpoint inhibition immunotherapy with PD-1 antibodies like cemiplimab have demonstrated response rates of the order of 40% and durability is encouraging: response duration was over a year in 75% of responders in the initial trial. We review the latest data with current immunotherapy drugs and consider the future directions such therapy may take us as well as the role of these therapies in special populations.