Neurodegenerative diseases affect millions of individuals worldwide. Among these, amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative condition caused by progressive loss of motor neurons leading to paralysis and death. So far, no disease-modifying drug is available to treat patients, making searching for effective drugs an urgent need. Investigation of ion channels in motor neurons unravelled a cluster of voltage-gated sodium (NaV) channel subtypes playing a vital role in the cortical hyperexcitability observed in pre-symptomatic stages of this disease. Spider-venoms are an exceptional source of peptides modulating NaV channels with higher potency and selectivity than small molecules such as the drug riluzole used in treating ALS. By systematically interrogating spider venoms via high throughput cellular screens and assay-guided fractionation, we have discovered spider-venom peptides targeting selectively ion channels in disease pathways and therefore have the potential to reverse complex neuronal pathologies. By modulating central NaV subtypes in motor neurons, ProTx-III, a peptide derived from the tarantula Thrixopelma pruriens, was able to induce similar effects as for riluzole in the reversal of hyperexcitability in motor neurons but with significantly higher potency and selectivity for NaV subtypes in motor neurons, and for more extended periods. ProTx-III significantly prevented the loss of motor function in a zebrafish model of motor neurodegeneration. This venom peptide is under optimization to generate multifunctional inhibitors that target only therapeutically relevant NaV subtypes in concert with ALS. We hope to contribute to developing venom-derived pharmacological tools for ion channel research and unravel the potential of spider peptides as novel drugs to aid the treatment of ALS.