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Ischemic stroke caused by atherosclerosis is associated with the highest risk of recurrence among stroke etiologies, highlighting a residual risk that current secondary prevention strategies fail to address. Multiple lines of research implicate inflammation in the pathogenesis of atherosclerosis, including recent large cardiovascular outcome trials demonstrating that anti-inflammatory therapies can lower residual vascular risk in patients with coronary artery disease. Notably, low-dose colchicine, a long-used anti-inflammatory drug, has received approval for cardiovascular risk reduction in patients with atherosclerosis. However, translation of anti-inflammatory treatments to patients with ischemic stroke has been challenging, with the first colchicine trials showing neutral or conflicting results. In this study, we review the preclinical, genetic, and epidemiologic literature linking inflammation to atherosclerotic stroke; examine key findings of cardiovascular outcome trials for stroke prevention; and summarize completed and ongoing stroke-specific trials. We discuss the etiologic heterogeneity of ischemic stroke that may obscure anti-inflammatory treatment effects, highlighting the need for precision medicine approaches targeting patients with established atherosclerosis and vascular inflammation. Finally, we provide an overview of the emerging anti-inflammatory therapeutics that are under development for atheroprotection and outline a translational roadmap to accelerate clinical impact in stroke prevention.