The voltage-gated sodium channel Nav1.7 is being heavily pursued as a potential target for the treatment of pain based upon strong human genetic validation. A safe and effective Nav1.7 targeting molecule would require appropriate selectivity over multiple other Nav1 subtypes. Peptide inhibitors of sodium channels isolated from spider venoms have in recent years received increasing attention as pharmacological tools and as lead molecules for medicinal chemistry optimization, due to their inherent selectivity towards Nav1.7 demonstrated in vitro. These cysteine-rich peptides, comprising an inhibitor cysteine-knot (ICK) structural motif, carry unique physico-chemical and pharmacological attributes and provide opportunities for improvement as drug-like molecules. This chapter reviews these attributes by discussing examples that demonstrate the state-of-the-art medicinal chemistry strategies being implemented in order to improve the potency, selectivity and ADME properties of these naturally derived ICK toxins. The ever-evolving mechanistic understanding, tractability and design of more potent and selective peptides which are reported in the efforts discussed suggest that there may be a path forward toward developing these peptides into pain therapeutics.