Facioscapulohumeral muscular dystrophy (FSHD) is a debilitating genetic condition manifest by weakness of facial and upper extremity musculature that presents in the 2nd decade of life. The causative genetic event is a contraction of a subtelomeric array of repeated 3.3 kb sequence units residing on one of two common alleles of chromosome 4. How this array contraction translates into cellular differences that result in weakness of select muscle groups is a fascinating question that is not presently understood. Each D4Z4 repeat unit contains a large open reading frame that encodes a putative double homeodomain containing protein named DUX4 making aberrant expression, or expression of aberrant DUX4 isoforms an attractive mechanism for FSHD pathology. Our long term objectives are to understand how muscle strength is compromised as a result of molecular events initiated by these contractions. With recent advances in our understanding of the pathogenesis of FSHD we have also begun to look for serum biomarkers that will allow us to more accurately track disease progression over short periods of time. Biomarker discovery is of paramount importance for quickly evaluating treatment strategies in clinical trials. Along these lines we are using RNA-seq in muscle cells and biopsies, and whole genome sequencing of cell free DNA present in serum to investigate both biomarker discovery and disease mechanism. We are tightly partnered with local advocate groups with the common goal of understanding this disease mechanism and facilitating treatment strategies through collaboration with pharmaceutical companies.