The Hedgehog family of ligands regulates a plethora of biological processes involved in embryonic development, tissue homeostasis and regeneration, and cancer progression. The canonical Hedgehog pathway is based on a series of de-repression events mediated by the proteins Patched, Smoothened, and Su(Fu) that allow a tightly controlled activation of the downstream transcription factors Gli1, Gli2, and Gli3. We and others have recently shown that Hedgehog, signaling through Smoothened, also activates Gi proteins/GRK2/arrestin, PI3K/Akt, and ERK signaling pathways which may have physiological significance on their own. In addition, Patched directly regulates cell cycle progression in a Hedgehog-dependent manner. These newly discovered events are grouped into the so-called non-canonical Hedgehog pathway.