Gene therapy has advanced rapidly over the last few decades due to the development of viral and plasmid vectors for gene delivery and strategies for the direct alteration of DNA/RNA species. Gene replacement using modified viral vectors and plasmids has yielded the greatest levels of therapeutic protein expression in muscle to date, however there are issues with immune mediated response to transgene and viral proteins, hindering sustained expression. New efforts have been made to make viral delivery of genes safer and sustainable, these include the development of hybrid vectors and "gutted" helper dependant vectors. Non-viral methods of gene delivery and repair provide an alternative to viral based methods. Major concerns with non-viral approaches include the effective distribution and integration of therapeutic molecules throughout the muscle. However, a number of methods have been developed to overcome these obstacles. These include electroporation, vascular injection and occlusion, myotoxins promoting muscle regeneration, muscle specific promoters and the use of pharmacological agents to enhance DNA delivery for gene delivery or gene repair. A number of non-viral plasmid based protocols for gene delivery to muscle have reached the clinical trial stage and show great promise. This review discusses recent advances in viral and non-viral based therapies for muscle diseases, the issues faced by these technologies and current efforts to overcome these obstacles. ©2006 Bentham Science Publishers Ltd.