How do small molecules exert their effects in mammalian cells? This seemingly simple question continues to represent one of the fundamental challenges of modern translational science and as such has long been the subject of intense scientific scrutiny. In their recent study, Garnett and colleagues (Gonçalves et al, 2020) demonstrate proof-of-concept for a new way to attack this problem systematically for Oncology drugs, by identifying correlated CRISPR- and drug-killing profiles in the Cancer Dependency Map dataset.