Insulin/relaxin superfamily peptides possess a complex structure comprising two chains and three disulfide bonds [1-7]. While recombinant expression systems can produce these peptides, they present several challenges, particularly in the correct folding of non-native analogues and the requirement for precise C-peptide cleavage for activity in some cases. Our team has developed innovative Solid-Phase Peptide Synthesis (SPPS) methods that overcome these limitations, enabling detailed structure–activity relationship studies. These advances have led to the design of simplified peptides and peptidomimetics that selectively target the G Protein-Coupled Receptors (GPCRs), Relaxin Family Peptide Receptors (RXFP1–4) [4-7]. Compared to the native peptides, these novel peptidomimetics are more amenable to synthesis (e.g. SPPS) in higher yields, exhibit improved receptor selectivity, and show enhanced proteolytic stability. The resulting peptidomimetics serve as powerful tools to investigate the GPCRs, RXFPs physiology and also represent promising drug leads for a range of conditions, including neurological, gastrointestinal, and metabolic disorders. This presentation will highlight the development of these novel chemical strategies and their application in designing therapeutic insulin [1-3] and insulin-like peptides [4-7].