Abstract: S u p e rox i d e d i s m u t a s e 1 ( S O D 1 ) i s a thermodynamically stable, zinc and copper binding homodimeric enzyme responsible for breaking down superoxide radicals. More than 200, mostly missense, mutations spread throughout the SOD1 gene are associated with the fatal neurodegenerative disease, amyotrophic lateral sclerosis (ALS). A unifying feature of ALS-associated SOD1 mutations is the destabilization of the SOD1 protein structure, increasing the propensity for misfolding and subsequent pathological aggregation. Post-mortem analysis of SOD1-associated ALS tissue shows the accumulation of misfolded SOD1 protein and ubiquitinated SOD1 inclusions within motor neurons. Misfolded SOD1 accumulation and aggregates are implicated in cellular dysfunction via a number of disparate but critical processes, including endoplasmic reticulum stress, oxidative damage, proteasome dysfunction, axonal transport abnormalities and synaptic dysfunction; culminating in motor neuron degeneration associated with ALS. As a result, misfolded and aggregated SOD1 is a primary target for therapeutic investigation in SOD1-associated ALS. Some of these approaches have shown preclinical and clinical promise, but often these therapies are targeted against a single component of disease. The cancer field has made great clinical strides utilizing a multi-pronged strategy to treat various forms of cancer. Patients are treated with a combination of multiple chemotherapy agents, radiation, surgery and/or immunotherapy to produce more effective therapeutic outcomes. In a similar manner, we propose that utilizing a multifaceted approach to target SOD1 across its pathogenic landscape may provide a highly feasible and more effective treatment approach.