Skin basal cell carcinoma (BCC) is caused by UV-light radiation activating the Hh signaling pathway through inactivating mutations in PTCH1 or activating events in SMO, as well as TP53 mutations. In this thesis we show that BCC is the tumor with the highest mutation rate to date with 65 mutations/Mb, and that its mutational signature of 90% C>T mutations in a pyrimidine context reveals clear UV-light causality. We show the relevance of downstream Hh genes and Hippo pathway genes in BCC by the identification of MYCN and PTPN14 point mutations. Additional genes such as LATS1, STK19, ERBB2, FBXW7, PPP6C, KNSTRN, and CASP8 were also mutated in a fraction of tumors. Gene expression studies support our finding that oncogenic mutations downstream of SMO and Hippo pathway activating mutations are alternative mechanisms in BCC. The results presented in this thesis enhance our understanding of tumorigenesis in BCC and provide the means for better classification of tumors and treatment options.