Significant work has already illuminated a vast array of A domain structures, both stand-alone and as part of a module, leading to an enhanced understanding of the molecular mechanisms required for activation of different classes of substrates. This has allowed for the determination of various substrate selectivity codes, which can be biochemically verified using a plethora of in vitro methods, and whose detection can be either chemical or instrumentational. Further, the continued curation of in silico algorithms and webtools provide a means to interrogate A domains and their predicted substrate scope using only genomic data, which continues to push natural product drug discovery towards a very bright future.