Antisense oligonucleotides are emerging as exciting therapeutic agents with the potential to overcome disease-causing mutations in the dystrophin gene. The size and complexity of the dystrophin gene allows for intervention during pre-mRNA processing, where selected exon excision can remove nonsense mutations or restore the reading frame disrupted by genomic deletions or duplications. This review summarizes some of the events leading up to forthcoming clinical trials in 2006, and speculates on some of the challenges facing targeted exon skipping as a therapy for Duchenne muscular dystrophy.