The Patched/Hedgehog pathway is one of the major signal transduction cascades implicated in developmental processes. Dysregulation of signaling has also been associated with several cancer forms, including Basal Cell Carcinoma, Medulloblastoma, Rhabdomyosarcoma and more recently cancers of the digestive track and the prostate. Here we provide an overview of experimental findings, which support the notion that the process of alternative pre-mRNA splicing, i.e. the capability of a gene to generate multiple mRNA variants, is inherently connected with the mechanisms that transduce the Hedgehog signal from the cell surface to the nucleus. This is especially obvious for Patched1, the transmembrane receptor of the Hedgehog ligands, and the transcription factor Glioma1, which acts on target genes as the terminal effector of signaling activation.