Clearly, the prospects are as big as the challenges. Recent reviews highlight the strong pharmaceutical potential of ncAA-supplemented drugs against various pathogens, e.g., MRSA, Acinetobacter baumannii, C. difficile, and Pseudomonas aeruginosa (Blaskovich, 2016; Hicks, 2016; Wang et al., 2016; Baumann et al., 2017). The modification of AMPs with new-to-nature ncAAs presents a versatile tool to fight the increasing lack of antimicrobial drugs (Blaskovich, 2016; Baumann et al., 2017). As the next stage, synthetic cells metabolically engineered to produce ncAAs in situ from simple chemical precursors are highly promising, especially for large-scale fermentation in industrial biotechnology (Völler and Budisa, 2017). Genetic code engineering and expansion complement traditional gene modification technologies, breaking the limitations in the number of building blocks and chemical diversity. This synthetic co-translational modification in combination with natural PTM machineries from diverse sources will become the method of choice to synthesize RiPP-based derivatives with novel and emergent properties.