Basal cell carcinomas and Squamous cell carcinomas are the two most common human cancers. The incidence of these two types of cancer is estimated to double within 20 years. Identification of the key molecular events is critical in helping us design novel strategies to treat and to prevent these cancers. For example, identification of hedgehog signaling activation has opened up many opportunities for targeted therapy and prevention of basal cell carcinomas. Significant progress has also been made in our understanding of squamous cell carcinomas of the skin. In this chapter, we will focus on major recent developments in our understanding of basal cell carcinomas and squamous cell carcinomas at the molecular levels and their clinical implications.