Melanoma, a malignant skin tumor, is the third skin tumor and the third cause of brain metastases. The development and introduction of systemic therapies, such as Braf inhibitors and checkpoint inhibitors, have guaranteed an increase in overall survival. The appearance of brain metastases, which determines a median survival of less than 5 months, represents a sign of systemic disease progression and tumor instability. In this view, in addition to systemic therapy, the therapeutic options can be surgery, stereotactic surgery, and whole-brain radiation therapy. However, it has been observed that the response to systemic therapies of brain metastatic lesions, compared to extracerebral ones, does not guarantee complete local tumor control, thus increasing the mortality and morbidity of patients. This phenomenon, tumor escape, makes systemic therapy partly ineffective. How melanoma cells migrate, cross the blood-brain barrier, and invade brain tissue is still being studied. The melanocytic metastatic brain tumor microenvironment and its assay seem to have a key role in the response and therefore in the progression of metastatic lesions. Through this work, the intent is to underline the importance of the brain tumor microenvironment and how it can influence tumor growth, its response to therapy, and the patient's overall survival.