As underscored by the 2018 Nobel Prize in Physiology for Medicine, immune checkpoint blockade (ICB) has revolutionized the management for a spectrum of advanced cancer types, both in the subsequent-line as well as first-line therapy settings. Since 2011, seven different agents targeting three different immune checkpoints have been approved by the US FDA. These include monoclonal antibodies against CTLA-4 (ie, ipilimumab), PD-1 (ie, nivolumab, pembrolizumab, and cemiplimab), and PD-L1 (ie, atezolizumab, avelumab, and durvalumab); now with FDA-approved indications for advanced and/or unresectable melanoma, non-small-cell lung carcinoma (NSCLC), head and neck and cutaneous squamous cell carcinoma, renal cell carcinoma (RCC), urothelial carcinoma, classical Hodgkin lymphoma, hepatocellular carcinoma, gastroesophageal adenocarcinoma, Merkel cell carcinoma, cervical adenocarcinoma, primary mediastinal B-cell lymphoma, and solid cancers with mismatch repair deficiency or high microsatellite instability. However, most of the initial ICB clinical trials had included disproportionately fewer patients with brain metastases (BMs) despite the increasing predilection for CNS metastases displayed by many cancer types. This was in part due to a number of challenges that face therapeutic trials for BMs, including concerns about: the blood–brain barrier (BBB) permeability of therapeutics; the potentially confounding effects of other treatment modalities often necessary for BMs (eg, whole-brain RT, stereotactic radiosurgery [SRS], or surgical resection), and that therapeutic efficacy might be diminished by the high-dose corticosteroids that are commonly needed to treat symptomatic cerebral edema. Historically, CNS metastases have proven particularly challenging to treat, with most therapeutic approaches providing minimal clinical benefit for patients–highlighting the need to explore the intracranial efficacy of novel new therapeutic modalities like immune checkpoint immunotherapy.