Peptide toxins isolated from spiders are potent inhibitors of human voltage-gated sodium channels (NaV). Some of these peptides are selective against subtypes NaV1.7, reported to be involved in nociception, and may thus have potential as pain therapeutic leads. Peptide toxins can inhibit NaV activity by blocking the pore domain (i.e, pore blockers) or by binding to the membrane-embedded voltage sensor domain of the sodium channel (i.e. gating-modifier toxins). It is now well established that some gating-modifier toxins also interact with lipid membranes surrounding the voltage-sensor domains. However, it is less well-known to what extent these peptide-lipid interactions are relevant for the inhibitory activity and/or sodium channel selectivity. Using a range of biophysical techniques, we have examined the importance of membrane binding on the inhibitory activity of a subset of peptides, showing a direct correlation between membrane binding affinity and NaV selectivity, highlighting the importance of considering potential membrane-binding events when designing sodium channel voltage-gating modifier inhibitors. Using this information, we have designed modified gating-modifier toxins with improved potency and off-target selectivity for the therapeutically relevant sodium channel subtype NaV1.7.