Tumor cells with constitutively active hedgehog signaling pathway can be treated with drugs that bind directly to and inhibit Smoothened. Unfortunately, the effect of these drugs does not last longer than 6 months before the tumor cells develop resistance. The responsible mechanisms include point mutations in the Smoothened-coding gene SMO, the amplification of the GLI2 gene or the amplification of one of the target genes of the hedgehog signaling pathway such as CCND1. In addition to drugs that bind directly to Smoothened, the hedgehog pathway can also be inhibited by compounds unfolding other effects. These include drugs that block the translocation of Smoothened to the cell membrane and through drugs that inhibit the activation of transcription by Gli.