Background: Despite the approval of effective therapies in metastatic melanoma, durable benefit concerns only a fraction of patients and new therapeutic options are still needed. Next generation sequencing is now widely available to screen for targetable genomic alterations. Clinical impact of personalized medicine strategies in melanoma, outside classical targeting, have little been reported yet. Methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all metastatic melanoma patients, aged 18 and over, for whom a molecular testing has identified one, or more, actionable molecular alterations and who received molecularly matched therapy accordingly, between 2018 and 2022. We excluded patients with only BRAF, NRAS or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Response was evaluated using RECIST 1.1 criteria. Results: We included 26 patients, median age was 63 years [24-89] and sex ratio 2.7. They had been heavily pretreated (58% have received 3 or more previous lines of treatment); 77% had 3 or more metastatic sites; 58% elevated LDH levels; and 42% and 35% had brain and liver metastasis respectively; 69 % had an ECOG PS 0 or 1. Actionable molecular alterations affected MAP kinase pathway in 12/26 cases: 10 of them received trametinib for GNA11 mutations (n = 4), MAP2K1 mutations (n = 2), CBL mutation (n = 1), NF1 loss (n = 1), FYCO1-RAF1 fusion (n = 1) and KRAS amplification (n = 1) while tipifarnib was given for an HRAS mutation and sunitinib for a CBL mutation. Cell cycle pathway was targeted in 7/26 cases with abemaciclib for a CDKN2A/B mutation, palbociclib for CDKN2A deletion, ribociclib and binimetinib for concurrent loss of CDKN2A and NRAS mutations (n = 2) and siremaldin and ribociclib for CCND1 amplification and MDM2/ CDK4 amplification (n = 2). PIK3CA pathway was targeted with alpelisib (n = 1) and with sirolimus for 1 PTEN mutation. EGFR, ALK and MET mutations were targeted using afatinib, alectinib and cabozantanib respectively. BRCA spectrum (ATM and BRCA1) was targeted with olaparib in 2 patients in combination with dabrafenib and trametinib for one patient who had relapsed under this therapy. 11/26 patients responded to this molecularly matched strategy with 4 partial responses and 7 stable diseases including 5 ≥ 6 months stable diseases, with a median follow-up of 8 months [1-54]. Among responders, median duration of response was 6.5 months [2.5-13] and 3 are still ongoing. Responding patients had GNA11 (n = 2), MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1 (n = 2), MDM2/ CDK4 and CDKN2A/NRAS (n = 2) alterations. Conclusions: High throughput sequencing followed by matched targeted therapy is a promising approach in metastatic melanoma patients refractory to approved treatments, underlying the importance of access to molecular testing and molecular tumor boards.