Description: Purpose: The mutation load in melanoma is generally high compared with other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinicopathologic features. Experimental Design: DNA was extracted from 34 fresh-frozen primary cutaneous melanomas and matched peripheral blood. Tumor histopathology was reviewed by two dermatopathologists. Exome sequencing was conducted and mutation rates were correlated with age, sex, tumor site, and histopathologic variables. Differences in mutations between categories of solar elastosis, pigmentation, and BRAF / NRAS mutational status were investigated. Results: The average mutation rate was 12 per megabase, similar to published results in metastases. The average mutation rate in severely sun damaged (SSD) skin was 21 per Mb compared with 3.8 per Mb in non-SSD skin ( P = 0.001). BRAF/NRAS wild-type (WT) tumors had a higher average mutation rate compared with BRAF/NRAS –mutant tumors (27 vs. 5.6 mutations per Mb; P = 0.0001). Tandem CC〉TT/GG〉AA mutations comprised 70% of all dinucleotide substitutions and were more common in tumors arising in SSD skin ( P = 0.0008) and in BRAF/NRAS WT tumors ( P = 0.0007). Targetable and potentially targetable mutations in WT tumors, including NF1 , KIT , and NOTCH1 , were spread over various signaling pathways. Conclusion: Melanomas arising in SSD skin have higher mutation loads and contain a spectrum of molecular subtypes compared with BRAF - and NRAS -mutant tumors indicating multigene screening approaches and combination therapies may be required for management of these patients. Clin Cancer Res; 19(17); 4589–98. ©2013 AACR .