The diversity and natural modularity of their biosynthetic pathways has turned natural products into attractive, but challenging, targets for synthetic biology approaches. Here, we discuss the current state of the field, highlighting recent advances and remaining bottlenecks. Global genomic assessments of natural product biosynthetic capacities across large parts of microbial diversity provide a first survey of the available natural parts libraries and identify evolutionary design rules for further engineering. Methods for compound and pathway detection and characterization are developed increasingly on the basis of synthetic biology tools, contributing to an accelerated translation of genomic information into usable building blocks for pathway assembly. A wide range of methods is also becoming available for accessing ever larger parts of chemical space by rational diversification of natural products, guided by rapid progress in our understanding of the underlying biochemistry and enzymatic mechanisms. Enhanced genome assembly and editing tools, adapted to the needs of natural products research, facilitate the realization of ambitious engineering strategies, ranging from combinatorial library generation to high-throughput optimization of product titers. Together, these tools and concepts contribute to the emergence of a new generation of revitalized natural product research.