Over the last 25+ years, the folate receptor (FR) has emerged as an attractive tumor biomarker with the potential to be exploited for therapeutic purposes. Increasing evidence suggests that this endocytosing protein can functionally mediate the cellular uptake and retention of natural folates, certain antifolates, and folate-drug conjugates; the consequences of the latter two events could result in biological modulation, including (but not limited to) tumor-targeted cytotoxicity. Because its tissue expression profile appears to be somewhat limited to either tissues responsible for whole body retention of folates (e.g., kidney and placenta), or certain pathologic tissues (e.g., tumors or activated macrophages), the FR is believed to be a useful biological target for disease management. Indeed, recent years have been peppered with reports of novel FR-targeted therapies, and many have demonstrated impressive in vivo potency, particularly against tumor xenografts, without the undesirable toxicity that often accompanies nontargeted drug regimens. This chapter will provide essential details on the properties of the FR, including where it is expressed and how it has been successfully manipulated for therapeutic benefit.