A large proportion of ischemic stroke and transient ischemic attack patients do not receive prompt and appropriate treatment with evidence-based, guideline-recommended, vascular risk reduction therapies when exposed to traditional care. Consequently, implementing effective strategies that can bolster the use of proven preventive therapies among persons with established cerebrovascular disease remains an important goal. The Stroke PROTECT (Preventing Recurrence Of Thromboembolic Events through Coordinated Treatment) program, which systematically implements 8 medication and behavioral secondary prevention measures, was significantly associated with increased treatment utilization at hospital discharge, as well as greater adherence, target biomarker control, and better clinical outcomes in the post-discharge setting. This award lecture paper presents the background, rationale, results, limitations and future directions of the original PROTECT program, depicts the progress and preliminary data from ongoing national and international PROTECT-based programs, and suggests potential next steps in the development and implementation of more empirically derived models geared at bridging the stroke prevention knowledge–evidence–practice chasm.