Stroke is responsible for almost 6 million deaths and more than 10% of all mortalities each year, and two-thirds of stroke survivors remain disabled. With treatments for ischemic stroke still limited to clot lysis and/or mechanical removal, new therapeutic targets are desperately needed. In this review, we provide an overview of the complex mechanisms of innate and adaptive immune cell-mediated inflammatory injury, that exacerbates infarct development for several days after stroke. We also highlight the features of poststroke systemic immunodepression that commonly leads to infections and some mortalities, and argue that safe and effective therapies will need to balance pro- and anti-inflammatory mechanisms in a time-sensitive manner, to maximize the likelihood of an improved long-term outcome. Stroke is the leading cause of death and disability globally. Two-thirds of stroke survivors are left disabled, requiring assistance in daily living tasks.Currently, treatments for ischemic stroke are limited to clot lysis and/or mechanical removal within a few hours of stroke onset.In addition to the brain injury and cell death that occurs rapidly due to severe cerebral ischemia, a secondary phase of infarct growth is driven by inflammation for several days.There are complex contributions from the innate and adaptive immune systems, but an improved understanding of this process may yield new therapeutic targets to limit stroke injury.