Human Sonic Hedgehog (SHH) encodes a 462 amino acid precursor protein. It undergoes autocatalytic internal cleavage to yield a non-glycosylated 19 kD N-terminal fragment, which has signaling activity, and a glycosylated 25 kD C-terminal protein that is active in precursor processing. The SHH N-terminal fragment is highly conserved between species with >98% amino acid identity between human, mouse, and rat. Lipid modifications of the SHH N-terminal fragment enhances its binding affinity and modulates interactions with the Patched and Smoothened transmembrane receptors. SHH activity is attenuated by its interaction with membrane-associated Hip. On the other hand, interaction with glycan can lead to the stimulation of SHH signaling. SHH is expressed in embryonic tissues that are critical for the patterning of early embryos. It functions as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. SHH regulates the differentiation and proliferation of early thymocyte progenitors and it also regulates the neural and hematopoietic stem cell fates. In adult tissues, SHH is associated with cancer development and tissue remodeling following injuries. Gastric SHH acts as a macrophage chemoattractant during the immune response to Helicobater pylori.