The (Pro)Renin Receptor, PRR, was initially identified as a component of the renin-angiotensin system (RAS) but new data have accumulated in 2010 that in a one hand confirmed PRR importance for tissue RAS, and in the other hand, revealed unexpected roles for PRR in development. Unlike its ligand renin, the gene called ATP6ap2/PRR is an ancestral gene extremely conserved during evolution and ATP6ap2/PRR homologs are found in organisms as remote from human as Drosophila, C.elegans and Ehrlichia chaffeensis that have no clear renin homologs. ATP6ap2/PRR is unique, located on the X chromosome of human and rodents and encodes a unique splice variant but PRR is submitted to an intracellular processing that, in addition to the integral membrane protein, generates a soluble form which is secreted in plasma and in urine and can be measured by an Elisa assay. It was shown that PRR-bound renin and prorenin display increased enzymatic activity and their binding activates intracellular signaling upregulating the expression of profibrotic proteins, explaining why most studies rushed to demonstrate a role of PRR in hypertension, in organ damage, and to identify PRR as a therapeutic target to optimize RAS blockade. The role of PRR in RAS activity in vitro has been unequivocally demonstrated by a crystal structure study showing that angiotensinogen exists under a reduced and an oxidized state and that the oxidized state was more susceptible to cleavage by renin especially when renin was bound to PRR. However, in spite of the existence of a link between a polymorphism in PRR gene and blood pressure, the role of PRR on the RAS activity in vivo has never been convincingly established because of the lack of true PRR antagonist and of PRR knock-out mice. When PRR expression was inhibited in Xenopus using morpholinos antisense, it provoked embryonic lethality, abnormal anterio-posterior patterning of the central nervous system and defective convergent extension movements in Xenopus gastrulae. Inhibiting PRR expression in Drosophila using small hairpin RNA under the control of a wing pouch promoter severely impaired wing development. The consequences of PRR inhibition in Xenopus and Drosophila are characteristic of impaired Wnt/ß-catenin and Wnt/Planar Cell Polarity signaling pathways and it was shown that, indeed, PRR was required for Wnt signaling pathways, in a renin-independent manner. With the generation of PRR floxed mice, late specific deletion in cardiomyocytes or in podocytes demonstrated a functional link between PRR and the vacuolar proton-ATPase and autophagy. When we crossed PRRflox/wt females with PGK-Cre males to delete PRR early in development, we found that PRR-/y is embryonic lethal. Then using mouse embryonic stem cells as a model to study the role of PRR during early development, we showed that PRR was necessary to maintain embryonic stem cell self-renewal and that this function is solely dependent on the soluble form of PRR. Thus, PRR appears to be a multifunctional protein, true partner of renin and increasing its enzymatic activity, functionally linked to vacuolar proton-ATPase and co-factor of the Wnt receptor complex. How, where and when are these functions regulated are essential questions we need to answer to fully understand the pathophysiological roles of PRR in embryonic stem cell biology, in development, in degenerative diseases including cancer, and finally, in the renin-angiotensin system.