In conclusion, the present review highlights how FSHD1 and FSHD2 should not be considered as distinct forms, and rather as part of a disease continuum characterized by a molecular spectrum of genetic and epigenetic factors, whose alteration plays a differential role on DUX4 repression and, subsequently, contributes to determining the FSHD phenotype. Here, DUX4 is linked to facioscapulohumeral muscular dystrophy.