Despite years of research and pioneering clinical work, stroke remains a massive public health concern. Since 1996, we have lived in the era of US Food and Drug Administration-approved intravenous (i.v.) recombinant tissue plasminogen activator (rtPA). This treatment, despite its promise, continues to exhibit its limitations. Endovascular therapy has several theoretic advantages over i.v. rtPA, including site specificity, longer treatment windows, and higher recanalization rates. In this article, we will review the various pharmacologic strategies for acute stroke treatment, providing both a historic context and the state of the art. The drugs will be classified on the basis of their theoretic rationale for therapy. Next, we will review the various devices and strategies for mechanical revascularization with an aim toward comprehensiveness. These range from wire disruption of thrombus to preclinical trials for novel mechanical solutions. This first installment of this 2-part series will end with an analysis of retrograde reperfusion techniques.