The present invention relates to the field of Hedgehog signalling, and more specifically to a cell-based assay system and methods for identifying inhibitors and/or antagonists of specific cellular events in said signalling pathway. The present invention hereby proposes a novel approach for identifying inhibitors and/or antagonists downstream of the signalling components Smoothened and Patched, e.g. at the Gli-level. The assay comprises cells lacking a functional Sufu protein, which according to the invention is a protein component of emerging importance in the Hedgehog signalling pathway.