Natural products that contain distinctive chemical functionality can serve as useful starting points to develop Nature’s compounds into viable therapeutics. Peptide natural products, an under-represented class of medicines, such as ribosomally synthesized and post-translationally modified peptides (RiPPs), often contain noncanonical amino acids and structural motifs that give rise to potent biological activity. However, these motifs can be difficult to obtain synthetically, thereby limiting the transition of RiPPs to the clinic. Aminovinyl cysteine containing peptides, which display potent antimicrobial or anticancer activity, possess an intricate C-terminal ring that is critical for bioactivity. To date, successful methods for the total chemical synthesis of such peptides are yet to be realized, although several advancements have been achieved. In this perspective, we review this burgeoning class of aminovinyl cysteine peptides and critically evaluate the chemical strategies to install the distinct aminovinyl cysteine motif.