Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease characterised by degenerative changes to both upper and lower motor neurons. It usually presents as a relentlessly progressive muscle atrophy and weakness, with the effects on respiratory muscles limiting survival to 2 to 4 years after disease onset in most cases. Current treatment options are based on symptom management and respiratory support, with the only approved medications prolonging survival for just a few months. A common feature in ALS is the cytoplasmic aggregation of proteins. Mutations in several ALS genes (including SOD1, FUS, TARDBP and C9ORF72) are known to lead to the pathological aggregation of their encoded proteins. The transactive response DNA-binding protein 43 (TDP-43) encoded by the TARDBP gene was identified in 2006 as a primary protein component of intracellular inclusions in most ALS cases, occurring in more than 90% of patients including those without mutations in TARDBP. This study has involved the development of antisense oligonucleotides (AOs) to modify expression of selected ALS-linked target genes, including SOD1, TARDBP and FUS using an exon skipping strategy. Knockdown of RNA transcripts has been achieved using AOs synthesized as 2’-O-methyl modified bases on a phosphorothioate backbone. The evaluation of second generation clinically applicable morpholino oligomers is underway to evaluate effects on RNA and protein expression, cell survival and protein aggregation. The development of AOs that selectively target mutated alleles will also be investigated. AOs have shown great potential as therapeutics in treating neurodegenerative diseases but remain underexplored for many potential ALS targets. This work could lead to improved therapeutics for subsets of ALS patients. The AOs developed could also be utilized as tools in functional studies to help elucidate disease mechanisms.