Purpose <p>Systemic therapies are increasingly being considered as primary treatments for brain metastases (BM), deferring the upfront use of local treatment modalities. However, evidence to support this paradigm shift is difficult to interpret given the volume of data published and the intricacies of the outcomes reported. The objective of this narrative review is to evaluate the current evidence guiding treatment selection for BM patients by assembling and analyzing a detailed dataset of clinical trials, completed and published during the last two decades.</p> Methods <p>Obstacles in interpreting the results of prospective systemic therapy clinical trials are detailed, including non-standardized study cohorts, inconsistent use of response assessment criteria, insufficient endpoint definition for central nervous system (CNS) efficacy, and under-reporting of previous radiotherapy. The paucity of prospective data to guide radiation therapy options is also addressed, and caveats of the available published evidence are detailed.</p> Results <p>Proposed treatment and follow-up recommendations for patient with newly diagnosed BM are provided based on currently available evidence.</p> Conclusion <p>Prospective trials evaluating contemporary treatment paradigms and defining the respective roles of systemic and local therapies are eagerly awaited.</p>