Increasing evidence suggests that the folate receptor (FR) can be exploited for therapeutic applications. This endocytosing protein is well known to functionally mediate the cellular uptake of natural folates, various antifolates, and folate-drug conjugates. The FR is also believed to be a useful biological target for disease management, because its tissue expression profile appears to be limited to tissues that are responsible for whole body retention of folates (eg, the placenta, choroid plexus and kidney) and, more importantly, to certain pathological tissues, such as tumors and sites of chronic inflammation. Recent reports of novel folate-targeted drug therapies have demonstrated impressive in vivo potency, particularly against tumor xenografts, without most of the undesirable toxicities that often accompany and plague non-targeted drug regimens. This review summarizes some important properties of the FR, including where it is expressed, and how it is being clinically manipulated with small-molecule conjugates of folate for diagnostic and therapeutic purposes related to cancer.