The molecular mechanism of the transport of long-chain fatty acids across cellular membranes and the necessity and precise functioning of specific proteins in this process are still unclear. Various alternative mechanisms have been proposed. Studies with artificial phospholipid bilayers support the concept that fatty acids may enter and traverse the plasma membrane without the involvement of proteins. On the other hand, a number of membrane-associated fatty acid-binding proteins (FABPs) have been described which putatively function as acceptors for fatty acids released from albumin or from lipoproteins. Albumin binding proteins located at the outer cell surface could play an additional role in the delivery of fatty acids. The subsequent transmembrane translocation of fatty acids could take place by a membrane protein acting as a translocase, or by simple diffusion of fatty acids through either the phospholipid bilayer or a pore or channel formed by one or more membrane fatty acid transporters. At the inner side of the plasma membrane, the fatty acid is bound to a cytoplasmic FABP, which serves to buffer the intracellular aqueous fatty acid concentration. The direction of fatty acid migration through the plasma membrane most likely is governed by the transmembrane gradient of fatty acid concentration, assisted to some extent and in selected tissues by co-transport of sodium ions. The intracellular transport of fatty acids from the plasma membrane to the sites of metabolic conversion (oxidation, esterification) or subcellular target (signal transduction) is greatly facilitated by cytoplasmic FABPs. In conclusion, cellular uptake and intracellular translocation of long-chain fatty acids is a multi-step process that is facilitated by various membrane-associated and soluble proteins. The mechanism of cellular uptake of fatty acids probably involves both a passive and carrier-mediated transmembrane translocation.