Background: MM is a highly targetable malignancy, with both kinase inhibitors and immunotherapies providing meaningful survival benefit. Different subtypes of mm harbor distinct GA that suggest targeted and immunotherapy options. Methods: Comprehensive genomic profiling was performed in 2,197 MMs for up to 315 cancer-related genes plus introns from 28 genes commonly rearranged in cancer on hybrid-capture, adaptor ligation-based libraries (mean coverage depth > 600X). TMB was calculated from ≥1.11 Mb sequenced DNA. We assessed base substitutions, insertions and deletions (short variants; SV), rearrangements, and copy number changes. Results: We assessed 6 subtypes: routine cutaneous (CT; 90%), desmoplastic (DM: 1%), acral lentiginous (AL; 1%), Spitzoid (SP; 1%), mucosal (MC; 2%) and ocular (OC; 5%). Each group harbored characteristic genomic signatures (Table). BRAFwas mutatedin 38% of CT of which 92% were SV GA and 8% were amplifications, fusions or cases with > 1 BRAF GA. High TMB in CT and DM is highly prevalent (42% and 83% with > 20 mut/Mb). BRAFGA were less common in AL (18%), MC (15%), and OC (2%). SP GA were dominated by fusions in BRAF (60%) and other kinases. KIT GA were prominent in MC and AL. TMB for MC and OC mm were very low. Key findings include novel drivers of BRAF inhibitor resistance including BRAFinternal rearrangements and kinase domain duplications. Conclusions: In the largest cohort of mm with NGS to date, genomic profiles and TMB differ across mm subtypes. Highly prevalent BRAF GA (including in the SP variant) and high TMB in CT and DM mm permit effective use of targeted and immunotherapies. Although MC and OC have lower BRAF GA frequency and lower TMB, targetable GA can be present. Novel BRAF inhibitor resistance mechanisms were observed.