Long a slogan for environmentalists, “think global, act local” could be a new rallying cry for biologists. As genome-wide techniques advance and their costs drop, scientists are expanding into larger and larger territories—metagenomics, global proteomic approaches, and analyses of thousands of genomes. These massive data sets are opening up new possibilities for understanding some of the smallest details of the genome. Here, we look at four such cases—investigating the evolutionary role of insertions and deletions in the genome, connecting an orphan enzyme with its gene, mapping the fine details of chromatin structure, and characterizing global interactions between proteins and RNA—all of which depend on a combination of global thinking and local action