Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been 
controversial over the last decades, progress in recent years has led to a model 
that incorporates these decades of findings and is gaining general acceptance in 
the FSHD research community. Here we review how the contributions from many labs 
over many years led to an understanding of a fundamentally new mechanism of 
human disease. FSHD is caused by inefficient repeat-mediated epigenetic 
repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in 
the variegated expression of the DUX4 retrogene, encoding a double-homeobox 
transcription factor, in skeletal muscle. Normally expressed in the testis and 
epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle 
induces expression of many germline, stem cell, and other genes that might 
account for the pathophysiology of FSHD. Although some disagreements regarding 
the details of mechanisms remain in the field, the coalescing agreement on a 
central model of pathophysiology represents a pivot-point in FSHD research, 
transitioning the field from discovery-oriented studies to translational studies 
aimed at developing therapies based on a sound model of disease pathophysiology.