For patients with metastatic melanoma, BRAF/MEK inhibitors (BRAF: B‑Raf proto-oncogene, serine/threonine kinase, MEK: Mitogen-activated protein kinase) and immune checkpoint inhibitors have significantly improved prognosis, with 5‑year survival rates of up to 50% and higher. In recent years, several phase II trials have shown that BRAF/MEK inhibitors and immune checkpoint inhibitors are also effective in brain metastases. The BRAF/MEK inhibitor combination dabrafenib plus trametinib achieves high intracranial disease control rates in both asymptomatic and symptomatic brain metastases, albeit with a shorter duration of response than in extracranial metastases. The immune checkpoint inhibitor combination nivolumab plus ipilimumab achieves high intracranial response rates with a durable treatment response for patients with asymptomatic brain metastases, although with limited efficacy for patients with symptomatic brain metastases. Resistance mechanisms of brain metastases and treatment of symptomatic brain metastases represent challenges requiring further research. Preclinical data suggest relevance of the PI3K-AKT and the OXPHOS pathways. Current clinical trials are investigating combinations with BRAF/MEK inhibitors and immune checkpoint inhibitors. Retrospective analysis suggests that the combination of stereotactic radiotherapy and immune checkpoint inhibitors achieves a survival benefit without increased toxicity compared to stereotactic radiotherapy or immune checkpoint inhibitors alone. This strategy is currently being investigated in several prospective studies. Interdisciplinary, multimodal management of brain metastases offers the opportunity to improve patient outcome and inspire clinical and translational research.