When the human genome was sequenced almost 20 years ago, many researchers were confident they’d be able to quickly home in on the genes responsible for complex diseases such as diabetes or schizophrenia. But they stalled fast, stymied in part by their ignorance of the system of switches that govern where and how genes are expressed in the body. Such gene regulation is what makes a heart cell distinct from a brain cell, for example, and distinguishes tumors from healthy tissue. Now, a massive, decadelong effort has begun to fill in the picture by linking the activity levels of the 20,000 protein-coding human genes, as shown by levels of their RNA, to variations in millions of stretches of regulatory DNA.