Recent advances in sequencing technology allow genome-scale approaches to cancer mutation discovery. Such data-intensive methods have been applied to cutaneous squamous cell carcinomas (SCCs) and melanomas but have not, to our knowledge, been applied to basal cell carcinomas (BCCs). We used whole-exome sequencing to characterize the mutational landscape of sporadic BCCs. We show that BCCs are the most mutated type of human cancer. Tumors from anatomical regions with chronic UV exposure were associated with higher mutation rates than those with intermittent exposure. The majority of all mutations (75.7%) were UV signature. Using a conventional binomial probability model, several genes were found mutated significantly. However, this model assumes a uniform distribution of mutations throughout the genome. We also used a more stringent approach called InVEx that uses a permutation-based framework to pick drivers from passengers. After correction for multiple hypothesis testing, InVEx identified only PTCH1 (Patched 1) as having a significant functional mutation burden. We also found three genes, STAT5B, CRNKL1, and NEBL, with mutational hot spots at a single base in 3 of 12 tumors sequenced. Our findings support the central role of PTCH1 mutations in BCC genesis. Moreover, our discovery of the uniquely high number of mutations in this tumor may lend insight into its biological behavior.