Blood biomarkers are increasingly beginning to play a role in the diagnosis, management, and prognostication of patients with acute ischemic stroke. While imaging biomarkers have played the largest role in determining acute therapies, blood-based biomarkers may have important contributions to make in settings where imaging is not readily available, or when making predictions about future complications and recurrent stroke. Though more research in large, diverse patient populations are needed before blood-based biomarkers become widely accepted for stroke management, preliminary reports suggest their value in several settings and the use of biomarkers is gaining traction. This article discusses the role of several selected readily available protein biomarkers in stroke diagnosis, acute management decisions, and prognosis. Protein biomarkers were primarily selected based on the fact that they have been evaluated in cohort studies and ideally that they have been validated by independent groups.