Australia has the highest rate of skin cancer in the world including cutaneous squamous cell carcinoma (SCC).  Although the vast majority are detected and treated at an early stage, some subsequently relapse with extensive loco-regional and/or distant metastatic disease.  Where loco-regional surgery and/or radiotherapy has failed, or is not feasible, systemic therapy should be considered.  Unfortunately, most systemic agents have had poor response rates.  This presentation highlights the evolving role of targeted systemic therapy for cutaneous SCC with particular reference to Epidermal Growth Factor Receptor (EGFR) inhibition.