We have had a long-standing interest in brain swelling after large hemispheric supratentorial hemispheric infarctions (LHI). Some of our early work, presentations, and publications were instrumental in changing the thinking about the mechanisms of deterioration after LHI and the ideal approach to medical management. We eventually accomplished funding from the National Institutes of Health for a multi-center clinical trial we designed and coordinated on the role of surgical decompression (hemicraniectomy) for brain swelling from LHI (HeADDFIRST).This was the first randomized, control clinical trial on the topic, and the design of this study was used to design several similar European trials on the same topic. The results of our trial, HeADDFIRST, demonstrated a set of criteria that sensitively discriminate between those patients with low and high mortality from LHI. It also showed that our medical treatment protocol accomplished the lowest mortality every reported in patients with strokes of this magnitude; half of that reported in the literature (including those patients in the recent European trial on the same subject that did not similarly standardize the medical treatment). We continue to explore the results of this study to develop new insights into how to better approach patients with this life-threatening complication.Our experience with hemicraniectomy and the surgical protocol we developed for the procedure has led our facility in discovering other patients who may benefit from this procedure. We have since published our application of this procedure in children with LHI as well as in patients with brain swelling from acute disseminated encephalomyelitis. In addition, we have since described and presented our series of patients with surgical decompression and insights on how to approach its more safe application with more uniform benefit to patients.