Urea is the major endproduct of protein metabolism in mammals. In carnivores and omnivores a large load of urea is excreted daily in urine, with a concentration that is 30 to 100 times above that in plasma (and even more in rodents). This concentrating activity is important for the sake of water economy. Several facilitated transmembrane urea transporters have been identified and their regulation and role in the urinary concentrating mechanism have been well documented. However, too little attention has been given to the existence of energy-dependent urea transport. At least three have been functionally described in the mammalian kidney (one in the proximal tubule and two in the collecting duct), but none of the transporters involved has been identified molecularly. This review first presents functional evidence for an energy-dependent urea secretion that occurs exclusively in the pars recta of the proximal tubule (proximal straight tubule, PST). This includes a high fractional excretion of urea, the demonstration of a large addition of urea into the "loop of Henle". This addition is abolished in rats treated with cisplatin, a drug known to induce a very selective damage in PST cells. This urea secretion is also supported by the direct measurement of urea transport in isolated PST, and by the description of familial azotemia, a genetic anomaly likely due to a loss of function of an active or secondary active transporter secreting urea into the nephron. Second, this review proposes a candidate transmembrane transporter responsible for this urea secretion in the PST. SLC6A18 is expressed exclusively in the PST and has been identified as a glycine transporter because of the very abundant loss of glycine in urine in SLC6A18 knock-out mice. We propose that it is actually a glycine/urea antiport, secreting urea into the lumen in exchange of glycine and Na. Glycine is most likely recycled back into the cell via a transporter located in the brush border. Several experimental observations that support this hypothesis are presented and discussed. This secretion of urea contributes to accumulate urea in the inner medulla and thus to reabsorb water more efficiently in the collecting ducts. It also reduces the rise in plasma urea concentration that occurs after intake of proteins. Even if urea is the least toxic of all nitrogen end-products, it has significant toxic effects mostly due to protein carbamylation, a chemical reaction that significantly reduces the function of these proteins, like does glycosylation in diabetes mellitus. By modifying the composition of the tubular fluid in the thick ascending limb, urea secretion in the PST contributes, indirectly, to influence the "signal" at the macula densa that plays a crucial role in the regulation of the GFR by the tubulo-glomerular feedback. Taking into account this secondary active secretion of urea in the mammalian kidney provides a new understanding of the influence of protein intake on GFR, of the regulation of urea excretion, and of the urine concentrating mechanism.