This chapter discusses the understanding of the biology of sry and sex determination particularly what is known of the biochemical basis of sry function and its relationship to the other genes in the sex determination pathway. Most importantly, it attempts to identify those areas, in which ignorance is greatest and address some of the issues that might concern the researchers in sex determination. Data discussed in this chapter, primarily from the studies of mice and humans; the symbol “sry” are used to refer exclusively to the murine gene and “sRY” to that of humans and other mammals. Two central tenets allow the geneticist to frame the question of the genetic basis of sex determination in mammals, in terms of which gene or genes on the Y chromosome are required for the initiation of testis development. The isolation of the predicted gene(s), known as the testis determining factor (TDF) in humans and testis-determining Y gene (Tdy) in mice, was the subject of an intense international research effort that culminated, with the identification of the human sry gene. Proof of the identity of sry and TDF came in the form of a chromosomally female mouse transgenic for the murine Sry gene: this mouse developed as a normal male, albeit sterile due to the presence of two X chromosomes and the absence of Y chromosomal genes required for spermatogenesis. Sry was thus, shown to be the only Y-linked gene (though by no means the only gene) required for testis determination in mammals.