Inappropriate expression of the double homeodomain protein DUX4 causes facioscapulohumeral muscular dystrophy (FSHD), but very little is known about its function. Both homeodomains of DUX4 show sequence similarity to the homeodomains of the muscle stem cell master regulators PAX3 and PAX7, and it has been shown that Pax3 and Pax7 antagonize the cell death phenotype of DUX4 in C2C12 cells. Now (p. 3685), Michael Kyba and colleagues investigate the homeodomains of DUX4 and their competitive interactions with other homeodomain-containing proteins. The authors show that the homeodomains of DUX4 are sufficient for repressing the master myogenic transcription factors MyoD and Myf5, thereby inhibiting differentiation, and that overexpression of MyoD suppresses this inhibition. Screening of related homeodomain proteins for suppression of DUX4 toxicity reveals that only Pax3 and Pax7 are able to compete with DUX4 to suppress pathogenic phenotypes. The authors next determine that although the homeodomain of Pax3 is essential for competition, it is not sufficient. Substituting the Pax7 homeodomain for that of DUX4, however, produces a chimeric protein that retains the pathological features of DUX4. These data highlight a unique relationship between the homeodomains of DUX4 and those of Pax3 and Pax7, and provide insight into the molecular function of DUX4.