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 tumor from healthy tissue. Now, a massive, decadelong effort has linked the activity level of the 20,000 protein-coding human genes, as shown by levels of their RNA, to variation in millions of stretches of regulatory DNA. By looking at up to 54 kinds of tissue in hundreds of recently deceased people, the $150 million Genotype-Tissue Expression project has begun to connect the dots of how our genome works. The analysis drives home just how convoluted the interconnections between genes and their regulatory DNA can be.