The sex of an individual is determined by the fate of the gonad. This organ arises from two different structures: the coelomic epithelium and a mesenchymal part that forms from the mesonephros. The early embryonic gonad can differentiate into a testis or an ovary, thus suggesting that at an early stage the gonad is bipotential. Testis formation requires differentiation of Sertoli cells, which will form the supporting cell lineage of the seminiferous tubules. These cells synthesize Anti-Mullerian Hormone (AMH), which induces regression of the Mullerian duct, thus counteracting the development of female internal genitalia. Moreover, Sertoli cells favor recruitment of other somatic cell lineages migrating from the mesonephros that are also crucial for testis development to occur. The interstitial area of the testis contains the steroidogenic cells (Leydig cells), which have the function of producing androgens. These hormones stimulate the differentiation of internal and external genitalia of the male [for a review see Gonad differentiation depends on the paternal transmission of the sex chromosome. Thus, an XY embryo develops as a male, whereas an XX embryo becomes female. Most of the genes involved in this developmental pathway have been discovered from genetic studies of human XY sex-reversal. At a molecular level, the Y chromosome encodes a testis determining factor, SRY [Sinclair et al., Key Words Abstract In mammals, the sex of the embryo is determined during development by its commitment either to the male or female genetic program regulating testicular or ovarian organogenesis. Major steps towards unraveling sex determination in mammals are achieved by the identification of key genes involved in human pathologies and the application of mouse genetics to analyze their function. While the expression of Sry and Sox9 is sufficient to induce the male developmental program, the molecular pathways that specify ovarian differentiation were unclear before the recent demonstration that mutations in the RSPO1 gene induce femaleto-male sex reversal in XX patients. By generating the corresponding mouse model, we have shown that Rspo1 is so far the earliest known gene controlling the female genetic developmental program. Rspo1 activates the canonical  -catenin signaling pathway required for female somatic cell differentiation and germ cell commitment into meiosis. The aim of this review is to describe the roles of R-spondins (Rspo) in developmental processes and disorders and the current knowledge obtained from murine models. A particular focus will be on Rspo1 and its crucial function in sex determination
