Going against the general consensus, scientists have unveiled an unexpected mechanism for sexual differentiation of critical reproductive structures during embryonic development. Every mammalian embryo, regardless of sex, possesses primitive reproductive tracts called the Wolffian and the Müllerian ducts. Around 16.5 embryonic days, one of the two ducts is maintained while the other degenerates: females retain the Müllerian duct, which differentiates into egg-delivering organs, and males retain the Wolffian duct, which eventually becomes sperm-carrying organs. In males, hormones called androgens sustain the Wolffian duct; thus, in females, Müllerian duct maintenance (and Wolffian duct degeneration), is thought to stem from a lack of these androgens. Now, Fei Zhao and colleagues demonstrate with mouse models that the hormone-sensing nuclear receptor COUP-TFII contributes to Wolffian duct degeneration independent of androgen activity. Without the Coup-tfII gene, female mice and male mice lacking testes (the source of androgens) retained Wolffian ducts, the authors found. As well, receptors for FGF, a growth factor for Wolffian duct formation, and one of the FGF-activated proteins, p-ERK, were increased in female Coup-tfII knockout mice, helping promote Wolffian duct retention. Taken together, Zhao and team's findings prompt reassessment of the role of androgens in reproductive duct selection. In a related Perspective, Amanda Swain further discusses the implications of Zhao et al.'s research, such as in studies of human reproductive disorders and defects.