Facioscapulohumeral dystrophy (FSHD; OMIM #158900, #158901) is caused by mis-expression of the DUX4 transcription factor in skeletal muscle 1 . Animal models of FSHD are hampered by incomplete knowledge of the conservation of the DUX4 transcriptional program in other species 2– 5 . Despite divergence of their binding motifs, both mouse Dux and human DUX4 activate genes associated with cleavage-stage embryos, including MERV-L and ERVL-MaLR retrotransposons, in mouse and human muscle cells respectively. When expressed in mouse cells, human DUX4 maintained modest activation of cleavage-stage genes driven by conventional promoters, but did not activate MERV-L-promoted genes. These findings indicate that the ancestral DUX4-factor regulated genes characteristic of cleavage-stage embryos driven by conventional promoters, whereas divergence of the DUX4/Dux homeodomains correlates with retrotransposon specificity. These results provide insight into how species balance conservation of a core transcriptional program with innovation at retrotransposon promoters and provide a basis for animal models that recreate the FSHD transcriptome.