The sonic hedgehog protein is involved in cancer progression. To identify new sonic hedgehog inhibitors, Petrova et al. screened for a small-molecule inhibitor of Hedgehog acetyltransferase, an enzyme involved in sonic hedgehog palmitoylation and regulation of sonic hedgehog signalling. From a series of hits generated from initial screens, four lead compounds were selected based on their potency and drug-like scaffold, one of which was shown to inhibit autocrine and paracrine sonic hedgehog signalling in cells.