The desire to achieve effective drug concentrations at a pathological site while using fractional systemic doses through arterial injections has challenged investigators for nearly a century. Arterial drug delivery is a pharmacological and bioengineering problem. Therefore, it is necessary to take a holistic overview of the subject. While the history of arterial injections is relatively short, the systemic and regional circulatory concepts that underpin it have ancient roots. This chapter elaborates on technological landmarks and explains key underlying concepts from a historical perspective. It includes a brief history of systemic and regional circulatory physiology; the history of angiography; the development of imaging tools, catheters, and contrast agents needed for effective arterial drug delivery; and the development of pharmacokinetic models, protocols, and carriers for oncologic and non-oncologic arterial delivery applications.