Ribosomally synthesized and post-translationally modified peptides (RiPPs) make up a rapidly growing superfamily of natural products. RiPPs exhibit an extraordinary range of structures, but they all begin as gene-encoded precursor peptides that are linear chains of amino acids produced by ribosomes. Given the gene-encoded nature of RiPP precursor peptides, the toolbox of protein engineering can be directly applied to these precursors. This Perspective will discuss examples of site-directed mutagenesis, noncanonical amino acid mutagenesis, and the construction and screening of combinatorial libraries as applied to RiPPs. These studies have led to important insights into the biosynthesis and bioactivity of RiPPs and the reengineering of RiPPs for entirely new functions.