Recent research has highlighted voltage-gated ion channels as promising therapeutic targets for complex neurological diseases. Although a significant number of ion channel modulators are available, spider-venoms are an exceptional source of peptidic ion channel modulators with higher potency and selectivity than small molecules. These venoms contain a wealth of cysteine-rich peptides that alter ion channel gating properties using a conserved modulatory mechanism via interactions with the voltage sensor domains that provide better subtype selectivity than small molecules. By systematically interrogating spider venoms via high throughput cellular screens and assay-guided fractionation, we have discovered spider-venom peptides that simultaneously target specific clusters of ion channels in disease pathways with the potential to reverse neuropathologies. In the peripheral nervous system, venom peptide Tap1a from the tarantula Theraphosa aphophysis reverts chronic visceral pain in an mice model of irritable bowel syndrome when administered intracolonically. In the central nervous system, venom peptide ProTx-III from the tarantula Thrixopelma pruriens reverts motor neuron hyperactivity associated with the early stages of neurodegeneration in motor neuron disease and rescued mobility in a zebrafish model of moto neurodegeneration. These venom peptides are amenable to peptide engineering via which optimized leads have been produced with enhanced in vitropharmacology and enhanced in vivo bioactivity. This research focuses on improving the predictability of in vivobeneficial effects from in vitro evaluations. We hope to contribute to the development of venom-derived pharmacological tools for ion channel research and help unravel the potential of spider-venom peptides in translational drug discovery.