The essential role of folates in cellular biochemistry is well established, but the nature of the participation by folate-binding proteins has been disputed. This review will define folate-binding proteins and distinguish them from low-affinity, nonspecific folate binders and folate-dependent intracellular enzymes. We outline changes in plasma folate-binding proteins in various clinical states, review their postulated functions, detail the biochemistry of mammalian soluble folate-binding proteins and their membrane-bound immunologically cross-reactive possible precursors, and present evidence that the latter proteins may function as the physiologic folate receptors and intracellular regulators of folate coenzyme availability.