Sex-lethal ( Sxl) is the sex determination switch in Drosophila , and also plays a critical role in germ-line stem cell (GSC) daughter differentiation in Drosophila melanogaster . Three female-sterile alleles at Sxl in Drosophila melanogaster were previously shown to genetically interact to varying degrees with the maternally inherited endosymbiont Wolbachia pipientis. Given this genetic interaction and W. pipientis’ ability to manipulate reproduction in Drosophila , we carried out a careful study of both the population genetics (within four Drosophila species) and molecular evolutionary analysis (across 20 Drosophila species) of Sxl . Consistent with earlier studies, we find that selective constraint has played a prominent role in Sxl’s molecular evolution within Drosophila , but we also observe patterns that suggest both episodic bursts of protein evolution and recent positive selection at Sxl . The episodic nature of Sxl’s protein evolution is discussed in light of its genetic interaction with W. pipientis .