Abnormal expression in skeletal muscle of the double homeobox transcription factor DUX4 underlies pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). Though multiple changes are known to be initiated by aberrant DUX4 expression, the downstream events initiated by DUX4 remain incompletely understood. In this study, we examined plausible downstream events initiated by DUX4. First, we found that nucleocytoplasmic protein export appeared to be decreased upon DUX4 expression as indicated by nuclear accumulation of a shuttle-GFP reporter. Second, building on studies from other labs, we showed that phospho(Ser139)-H2AX (γH2AX), an indicator of double-strand DNA breaks, accumulated both in human FSHD1 myotube nuclei upon endogenous DUX4 expression and in Bax-/-;Bak-/- (double knockout), SV40-immortalized mouse embryonic fibroblasts upon exogenous DUX4 expression. In contrast, DUX4-induced caspase 3/7 activation was prevented in Bax-/-;Bak-/- double knockout SV40-MEFs, but not by single knockouts of Bax, Bak, or Bid. Thus, aberrant DUX4 expression appeared to alter nucleocytoplasmic protein transport and generate double-strand DNA breaks in FSHD1 myotube nuclei, and the Bax/Bak pathway is required for DUX4-induced caspase activation but not γH2AX accumulation. These results add to our knowledge of downstream events induced by aberrant DUX4 expression and suggest possibilities for further mechanistic investigation.