Covering: 2000 to 2019Natural products (NPs) are important sources of human therapeutic agents and pesticides. To prevent self-harm from bioactive NPs, some microbial producers employ self-resistance genes to protect themselves. One effective strategy is to employ a self-resistance enzyme (SRE), which is a slightly mutated version of the original metabolic enzyme, and is resistant to the toxic NP but is still functional. The presence of a SRE in a gene cluster can serve as a predictive window to the biological activity of the NPs synthesized by the pathway. In this highlight, we summarize representative examples of NP biosynthetic pathways that utilize self-resistance genes for protection. Recent discoveries based on self-resistance gene identification have helped in bridging the gap between activity-guided and genome-driven approaches for NP discovery and functional assignment.