<b><i>Background:</i></b> The establishment of male or female identity (sex determination) is essential for creating the anatomical, physiological, and behavioral differences between 2 sexes of the same species (sexual dimorphism). In many organisms, including mammals and <i>Drosophila</i>, sex is determined by inheritance of sex chromosomes, while in other animals, sex is determined by environmental factors. Arguably the most important consequence of sex determination is the production of healthy gametes necessary for reproduction: female oocytes and male spermatids. <b><i>Summary:</i></b> The generation of sperm and oocytes requires cooperation between 2 different cell types within the gonad: germ cells and somatic cells. Defects in sex determination in either the somatic gonad or germline lead to disorders of sexual development and infertility. In <i>Drosophila</i>, the gene <i>Sex lethal (Sxl)</i> is the key determinant of sex in both the soma and the germline. However, how <i>Sxl</i> controls sex determination is much more well understood in the soma than the germline. <b><i>Key Mesage:</i></b> This review will focus on <i>Sxl</i> in the germline, how it is activated specifically in female germ cells, and how it regulates germline sex determination and sexual development.