Folic acid, also known as vitamin B9 (Fig. 9.1), is an essential co-enzyme in one-carbon metabolism pathways, including the biosynthesis of nucleotides (i.e. purines, thymidine) and several amino acids. In general, two functionally different systems mediate the cellular uptake of folate: (1) the reduced folate carrier (RFC, Kd ∼ 10-6 M), an anion transporter that delivers folates across the plasma membrane in a bidirectional fashion, and (2) the folate receptor (FR, Kd ∼ 10-10 M), which internalizes folate through active receptor-mediated endocytosis. The RFC, a membrane-spanning anion transporter, is present in virtually all tissues and is responsible for the majority of folate transport in and out of cells. In contrast, FR expression is largely restricted to malignant cells, activated macrophages, and the proximal tubule cells of the kidneys. Because a variety of important diseases are caused by the former two cell types, interest in exploiting FR for drug targeting applications has rapidly increased. And achievement of this targeting objective, primarily through conjugation of drugs to folic acid is believed to enable (1) enhanced net drug uptake by pathologic cells, and more importantly (2) reduction in drug deposition into non-pathologic cells, thereby mitigating collateral toxicity to normal tissues.