Approximately 50% of all cutaneous melanomas harbor activating BRAF V600 mutations; among, these 10–30% carry the V600K mutation. Clinically, patients with V600K tumors experience distant metastases sooner and have an increased risk of relapse and shorter survival than patients with V600E tumors. Despite the clinical and other histopathological differences between these BRAF tumor subtypes, little is known about them at the genomic level. Herein, we systematically compared BRAF V600E and V600K skin cutaneous melanoma (SKCM) samples from the Cancer Genome Atlas (TCGA) for differential protein, gene, and microRNA expression genome-wide using the Mann–Whitney U-test. Our analyses showed that elements of energy-metabolism and protein-translation pathways were upregulated and that proapoptotic pathways were downregulated in V600K tumors compared with V600E tumors. We found that c-Kit protein and KIT gene expressions were significantly higher in V600K tumors than in V600E tumors, concurrent with significant downregulation of several KIT-targeting microRNAs (mir) including mir-222 in V600K tumors, suggesting KIT and mir-222 might be key genomic contributors toward the clinical differences observed. The relationship that we uncovered among KIT/c-Kit expression, mir-222 expression, and growth and prosurvival signals in V600 tumors is intriguing. We believe that the observed clinical aggressiveness of V600K tumors compared to V600E tumors may be attributable to the increased energy metabolism, protein translation and prosurvival signals compared with V600E tumors. If confirmed using larger numbers of V600K tumors, our results may prove useful for designing clinical management and targeted chemotherapeutical interventions for BRAF V600K-positive melanomas. Finally, the small sample size in V600K tumors is a major limitation of our study.