The generation of sexually dimorphic traits depends on highly conserved DM domain-containing transcription factors, including, in Drosophila melanogaster, Doublesex (Dsx) – which has male- and female-specific isoforms (DsxM and DsxF, respectively). Rohit Joshi and his team now investigate how Dsx causes female-specific apoptosis in a small set of terminal neuroblasts (tNBs) in the Drosophila central nervous system. They find that tNBs express both Dsx and Abd-B, a Hox gene that drives expression of Dsx in a sex-independent manner. Furthermore, they show that a highly conserved homeodomain of AbdB directly binds to the DM region of Dsx, which is common to both male and female isoforms. They also demonstrate that AbdB initially functions as a repressor of the pro-apoptotic genes grim and reaper, until its cooperative binding with DsxF on the apoptotic enhancer converts it into an activator to promote tNB apoptosis. In contrast, DsxM and AbdB do not exhibit cooperative binding on the apoptotic enhancer, thereby preventing tNB apoptosis in males. Collectively, these results indicate that the sex-specific utilisation of Dsx as a transcriptional cofactor for AbdB promotes apoptosis of a subset of tNBs in females and may point towards a novel mechanism to establish sexual dimorphism.