Covering: up to 2021Self-resistance mechanisms adopted by natural product producers have long been recognized and studied as a standalone system separated from the assembly machinery. However, as more examples of self-resistance have been characterized in detail, it has been revealed that self-resistance could associate with the assembly machinery to fulfill the task of biosynthesis. This review summarizes different self-resistance mechanisms showing a common feature: intersection with natural product assembly. Furthermore, their possible evolutionary origin and synthetic biology applications are discussed.