DUX4 is a transcription factor with a critical role in zygotic genome activation. It is expressed briefly in early embryogenesis and shut off for the rest of life. Inappropriate reactivation of DUX4 in adult muscle cells causes facioscapulohumeral dystrophy (FSHD), a muscular dystrophy affecting up to 1 in 8000, currently with no cure. In healthy adults, DUX4 is kept repressed through a variety of epigenetic mechanisms. Here, we explore the regulation of DUX4 in both embryogenesis and adulthood to identify similarities and differences. Comparative insights into DUX4 regulation can also be gained by studying its mouse homologue, Dux, which plays a similar role in early embryogenesis. Despite being in different genomic environments, Dux and DUX4 share similar regulatory mechanisms. We propose that the mechanisms regulating Dux and DUX4 in embryogenesis could inspire novel therapeutic angles for FSHD.