Over the past decades, continuous technological advances and the availability of novel therapies have enabled treatment of more acute medical conditions than ever before. Many of these treatments, such as intravenous thrombolysis and mechanical thrombectomy for acute ischemic stroke, are highly time sensitive. This has raised interest in shifting advanced acute care from hospitals to the prehospital setting. Key objectives of advanced prehospital stroke care may include (1) early targeted treatments in the prehospital setting, for example, intravenous thrombolysis for acute stroke, and (2) advanced prehospital diagnostics such as prehospital large vessel occlusion and intracranial hemorrhage detection, to help inform patient triage and potentially reduce subsequent workload in emergency departments. Major challenges that may hamper a swift transition to more advanced prehospital care are related to conducting clinical trials in the prehospital setting to provide sufficient evidence for emergency interventions, as well as ambulance design, infrastructure, emergency medical service personnel training and workload, and cost barriers. Utilizing new technologies such as telemedicine, mobile stroke units and portable diagnostic devices, customized software applications, and smart storage space management may help surmount these challenges and establish efficient, targeted care strategies that are achievable in the prehospital setting. In this article, we delineate the paradigm of shifting advanced stroke care to the prehospital setting and outline future directions in providing evidence-based, patient-centered prehospital care. While we use acute stroke as an illustrative example, these principles are not limited to stroke patients and can be applied to prehospital triage for any time-critical disease., Competing Interests: Disclosures Dr Ospel is a consultant for Nicolab. Dr Goyal holds grants from Johnson & Johnson and Medtronic and is a consultant to Medtronic, Mentice, Microvention, Philips, and Stryker. Dr Saver reports personal fees from Medtronic, Rapid Medical, Phenox, BrainsGate, Bayer, Roche, Genentech, Novo Nordisk, and CSL Behring. Dr Fisher is a staff neurologist at Beath Israel Deaconess Medical Center and consultant to Lumosa. Dr Fladt holds a grant from the Swiss National Science Foundation (Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung). Dr Saver is a consultant to Abbott Laboratories, Aeromics, Biogen, Boehringer Ingelheim, BrainQ, Brainsgate, Johnson & Johnson Healthcare Systems, Medtronic USA, MindRhythm, MIVI Neuroscience, Neuronics Medical, Rapid Medical, and Roche. The other author reports no conflicts.