Delivering early, robust hints of potential efficacy is one of the most daunting challenges in drug development. No matter how good the theoretical and preclinical rationale, in the end it is only a large-scale ‘experiment in man’, a phase 3 trial, that ultimately resolves biological cause-effect relationships in a disease process, and thereby proves/disproves a new target and establishes a new therapeutic. Can high-complexity systems-level biological data, derived as close as possible to first-in-man application of an experimental drug, help de-risking development, for both company and patients alike, by selecting likely winners early-on? In this issue of Gastroenterology, Schreiber and colleagues demonstrate an impressive and commendable case of how such a strategy could look like in inflammatory bowel disease (IBD).1