For biologists, meeting today’s greatest scientific challenges—confronting a warming planet, fighting debilitating diseases, or tracking the evolution of a genome—requires a new kind of science. It relies on an understanding of the dynamics and interconnectivity of systems, from our inflammatory system to ecosystems. Making the tiniest alterations in a system can lead to sweeping, often unintended consequences—like drugs with severe side effects or environmental regulations that backfire. Now, thanks to new technologies and immense computing power, biologists are better able to understand the complexity of these systems, and how all the diverse parts work together. Practitioners call such big-picture, technology-enabled approaches “systems biology,” and this is the story of three CAS scientists at the leading edge of discovery.