Melanoma has a high propensity to metastasize to the brain, and patients with melanoma brain metastases (MBM) have an extremely poor prognosis. The recent approval of several molecularly-targeted agents (e.g., BRAF, MEK inhibitors) and biologics (anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies) has brought new hope to patients suffering from this formerly untreatable and lethal disease. Importantly, there have been recent reports of success in some clinical studies examining the efficacy of both targeted agents and immunotherapies that show similar response rates in both brain metastases and extracranial disease. While these studies are encouraging, there remains significant room for improvement in the treatment of MBM, given the lack of durable response and the development of resistance to current therapies. Critical questions remain regarding mechanisms that lead to this lack of durable response and development of resistance, and how those mechanisms may differ in systemic sites versus brain metastases. One issue that may not be fully appreciated is that the delivery of several small molecule molecularly-targeted therapies to the brain is often restricted due to active efflux at the blood-brain barrier (BBB) interface. Inadequate local drug concentrations may be partially responsible for the development of unique patterns of resistance at metastatic sites in the brain. It is clear that there can be local, heterogeneous BBB breakdown in MBM, as exemplified by contrast-enhancement on T1-weighted MR imaging. However, it is possible that the successful treatment of MBM with small molecule targeted therapies will depend, in part, on the ability of these therapies to penetrate an intact BBB and reach the protected micro-metastases (so called “sub-clinical” disease) that escape early detection by contrast-enhanced MRI, as well as regions of tumor within MRI-detectable metastases that may have a less compromised BBB. The emergence of resistance in MBM may be related to several diverse, yet interrelated, factors including the distinct microenvironment of the brain and inadequate brain penetration of targeted therapies to specific regions of tumor. The tumor microenvironment has been ascribed to play a key role in steering the course of disease progression, by dictating changes in expression of tumor drivers and resistance-related signaling mechanisms. Therefore, a key issue to consider is how changes in drug delivery, and hence local drug concentrations within a metastatic microenvironment, will influence the development of resistance. Herein we discuss our perspective on several critical questions that focus on many aspects relevant to the treatment of melanoma brain metastases; the answers to which may lead to important advances in the treatment of this devastating disease.