Facioscapulohumeral muscular dystrophy (FSHD) is a muscle degenerative disease that disproportionally affects the muscles of the face, shoulder girdle and upper arms. FSHD is caused by the ectopic expression of Double Homeobox 4 (DUX4), which has been derepressed due to aberrant genetic and epigenetic events. DUX4 expression is normally tightly regulated and restricted to the thymus, testis and early cleavage stage embryos. Misexpression of DUX4 in skeletal muscle underlies the pathogenesis of FSHD. The expression of DUX4 in FSHD-affected tissue is low, with both transcript and protein proven difficult to detect. Yet when mis-expressed, this low expression can have great implications, which is evident in patients suffering from FSHD. To gain insight into the pathophysiology of FSHD, we aimed to identify DUX4 downstream targets leading to DUX4-induced cytotoxicity and assess if manipulation of downstream targets could potentially mitigate DUX4 cytotoxicity. We did so by developing a DUX4 inducible cell line that upon DUX4 expression recapitulates the FSHD transcriptional signature and ultimately undergoes apoptotic cell death, and subsequently analyzing this cell model with RNA sequencing, and CRIPSR/Cas9 knock-out screens. We’ve identified early DUX4 regulated genes, and the sequence of events that follows directly after the induction of DUX4. No obvious key effectors other than DUX4 itself were identified, suggesting treatment efforts for FSHD should be directed towards its direct modulation.