Over the past decade, the landscape of systemic therapy has been transformed by the arrival of immunotherapy and highly effective targeted agents. Many of these drugs have significant intracranial activity, creating a new and complex challenge for the radiation oncologist: how do we sequence our treatments? The old paradigm of "radiation first" is no longer always correct. Today, we will provide a modern guide to navigating this new reality. We will discuss when it's appropriate to defer radiation entirely, compare the CNS efficacy of different systemic regimens, and detail the critical safety considerations and toxicity risks of combining SRS with these powerful new drugs.