Mammalian sex differentiation involves the action of a cascade of genes. Discovery of the sex-determining region of the Y chromosome (SRY) marked the beginning of the delineation of the genes in the cascade. Studies of the genetics of mammalian sex reversal and the embryogenesis of the mice are essential in this endeavor. A number of genes involved in the pathway have been identified and all except one of these genes have a putative role in male sex differentiation. Besides SRY being the master switch in male sex differentiation the hierarchical relationship of the genes identified are far from being understood. Similarly, our knowledge of the genetic regulation of female sex differentiation is minimal. Differential screening and gene expression profiling bring a new dimension to the pursuit with the identification of a number of genes previously unknown to be involved in sex differentiation. Wider application of functional genomic techniques and introduction of proteomic analyses are expected to shed light to our understanding of this complicated developmental process.