Cone snail venom has been the most abundant source for natural peptide modulators of the nicotinic acetylcholine receptors. α-Conotoxins from cone snail venom is the largest family of peptide inhibitors of the nAChRs. These are 17-20 amino acid long, two disulfide bonded peptides that inhibit the receptor via the endogenous ligand binding pocket (orthosteric ligand binding site). Despite a conserved disulfide framework, three-dimensional structure and mechanism of action, α-conotoxins vary considerably in their primary sequence, which drive their distinct potency and selectivity profiles at the various nAChR subtypes. Their relative ease of synthesis, has facilitated extensive structure-activity studies, which have provided some crucial insights into the orthosteric ligand recognition properties of the nAChRs. Chemical modifications to the natural scaffold such as amino-acid substitutions, backbone cyclization, replacement of disulfide bridges with dicarba linkers and lipophilic analogues have further improved the native pharmacological properties, proteolytic resistance, synthetic yields and bioavailibitlity, making α-conotoxins amenable to therapeutic applications. In addition to α-conotoxins, the cone snail venom has proven to be a source of an array of nAChR modulators from nine superfamilies’ that vary significantly in their primary sequence, structure and potentially mode of action (A, B3, D, L, M, O1, S, T and J). Demonstrating that cone snail venom can provide structurally and functionally distinct classes of peptide nAChR modulators as templates for alternate rational strategies in drug design. This project focuses on delineating the structural mechanisms underlying the mode of action of some of these atypical conotoxins targeting the nAChRs.