This chapter discusses clinical trials in acute ischemic stroke. The main purpose of acute stroke therapy is to reduce death and disability. Surrogate markers, biomarkers that capture the full major effects of a treatment are used to substitute for clinical outcome measures. Studies using individual level patient data from randomized controlled stroke trials demonstrated that tests that maintain the ordinal level of data are typically more efficient than treating functional outcome measures dichotomously. Early middle phase studies are also needed to determine safety and to gain information on efficacy. Recruitment in acute stroke trials is a challenge for many reasons. The technology of mechanical thrombectomy is evolving faster than the technologies can be tested adequately in clinical trials. Rigorous clinical trial design is needed to progress new therapies through early, middle, and late development in order to identify efficiently a new treatment for acute ischemic stroke.