Melanoma is the most lethal skin malignancy that comprises clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, better results in melanoma treatment have been achieved with mutation-specific inhibitors that were developed for clinical use and target only patients with particular tumor genotypes. The aim of this study was to characterize the spectrum of driver mutations in melanoma subtypes from 137 patients with cutaneous melanoma and 14 patients with mucosal melanoma. In the total of 151 melanoma cases, the frequencies of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations were 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV-exposure and in 43% of cutaneous melanoma with chronic UV exposure (p = 0.045), rarely in acral and mucosal melanomas. Most melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to the BRAF inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas, the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and in mucosal melanoma (28.6%), but not in acral melanoma. Most KIT mutations were located in exon 11, and such tumors are sensitive to tyrosine kinase inhibitors. This study has been the first screening for BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma in a Russian population. Our data indicate that, on the molecular level, melanoma is a heterogeneous malignancy that should be tested for driver mutations in each case to determine its potential sensitivity to targeted therapy. The results were important for the rational design of melanoma therapy and were used in the treatment of melanoma patients.