Metastatic melanoma is a highly aggressive disease. Recent progress in immunotherapy (IT) and targeted therapy (TT) has led to significant improvements in response and survival rates in metastatic melanoma patients. The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerland. This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors, and kinase inhibitors from January 2008 until December 2014. The 1-year survival was 69% (n=121) in patients treated with checkpoint inhibitors (IT), 50% in patients treated with TTs (n=113), 85% in the IT+TT group (n=66), and 38% in patients treated with standard chemotherapy (n=95). The median overall survival (mOS) from first systemic treatment in the entire study cohort was 16.9 months. mOS of patients treated either with checkpoint or kinase inhibitors (n=300, 14.6 months) between 2008 and 2014 was significantly improved (P<0.0001) compared with patients treated with standard chemotherapy in 2008–2009 (n=95, 7.4 months). mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV (n=334), therefore being significantly different (P=0.00065). Furthermore, a significant reduction in hospitalization duration compared with chemotherapy was noted. Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospective trial data.