Targeted therapies for melanoma and basal cell carcinoma have evolved from deciphering the molecular mechanisms involved in their tumorigenesis. Mutations in BRAF have led to clinical use of BRAF-inhibitors in advanced melanoma, and mutations in Hedgehog signaling to smoothened inhibitors in basal cell carcinoma. The development of tumor resistance to these treatments is leading to many new drug development initiatives and the exploration of multiple signalling pathways. Cutaneous squamous cell carcinoma continues to rise steeply in incidence with very limited therapeutic options for locally advanced or metastatic disease. New genetic technologies find significant levels of mutation in Notch gene family as well as other already recognized gene mutations, such as TP53. The mutational burden in cutaneous squamous cell carcinoma is massive, challenging the identification of driver genes and inhibiting translation from genomics to the clinic. Clinical experience with targeted therapies, such as epidermal growth factor receptor inhibitors, or immune modulatory drugs suggests that these agents may be of benefit to patients, while a more complete understanding of the mechanisms behind squamous cell carcinogenesis awaits further progress.