Constantly evolving drug-resistant “superbugs” have caused an urgent demand for novel antimicrobial agents. Natural products and their analogs have been a prolific source of antimicrobial agents, even though a high rediscovery rate and less targeted research has made the field challenging in the pre-genomic era. With recent advancements in technology, natural product research is gaining new life. Genome mining has allowed for more targeted excavation of biosynthetic potential from natural sources that was previously overlooked. Researchers use bioinformatic algorithms to rapidly identify and predict antimicrobial candidates by studying the genome before even entering the lab. In addition, synthetic biology and advanced analytical instruments enable the accelerated identification of novel antibiotics with distinct structures. Here, we reviewed the literature for noteworthy examples of novel antimicrobial agents discovered through various methodologies, highlighting the candidates with potent effectiveness against antimicrobial-resistant pathogens.