The therapeutic management of melanoma brain metastases has undergone a profound revolution during recent decades. Optimal integration of systemic therapies with local treatments seems to represent the strategy to pursue in order to maximize clinical outcomes, stressing the need for real multidisciplinary care in this setting of patients. However, the current approach in the clinics does not necessarily reflect what the current guidelines state, and several pending issues are present, from the ideal therapeutic sequence between stereotactic radiosurgery (SRS) and drug administration to the current role of surgery and whole brain radiotherapy (WBRT), all of which need to be addressed. This narrative review aims to provide practical help for navigating the current controversies, with an eye towards possible future advancements in the field, which could help to obtain a comprehensive molecular characterization of the tumor and a more personalized patient-centered therapeutic approach.

Melanoma brain metastases (MBM) remain a major therapeutic challenge, requiring a multidisciplinary approach integrating systemic and local therapies. The advent of immune checkpoint inhibitors and targeted therapies has markedly improved patients’ survival, with the combination of ipilimumab and nivolumab now considered as first-line systemic treatment for patients with asymptomatic MBM. Radiotherapy plays a crucial role, with stereotactic radiosurgery (SRS) now preferred over whole-brain radiotherapy (WBRT), due to its efficacy and lower risk of neurocognitive impairment. Retrospective data support a potential synergy between systemic therapy and SRS and emerging clinical evidence suggests that this combined approach may offer enhanced disease control and could become the standard of care. Key unresolved questions include the ideal sequencing of SRS with systemic treatments, the optimal radiation dose to balance efficacy and neuroprotection, and the identification of predictive biomarkers to refine patient selection. Emerging research focuses on tumor microenvironment interactions and novel radiosensitizers to enhance therapeutic outcomes. Furthermore, artificial intelligence-driven models integrating radiomics, radiogenomics, and metabolomics hold promise for advancing precision medicine in MBM management. Ongoing prospective clinical trials are crucial to establishing standardized treatment guidelines, ensuring a personalized, patient-centered approach that optimizes survival while preserving quality of life.