Left: In the absence of Hedgehog protein, the transmembrane protein Patched (purple) inhibits the transmembrane receptor protein Smoothened (blue and grey) via an unknown mechanism. The findings of Luchetti et al. and Huang et al. suggest that Patched and Smoothened may communicate using the lipid molecule cholesterol (green), which is a core component of animal cell membranes (orange lines). Patched is similar to other proteins that transport small molecules across membranes, and might act to limit cholesterol access to Smoothened. In the absence of available cholesterol, Smoothened receptors on the cell surface are inactive. Right: Hedgehog protein binds to and inactivates Patched, potentially increasing cholesterol levels outside the cell. Cholesterol binds to a hydrophobic pocket in the Smoothened cysteine-rich domain (blue). Smoothened can now activate the Hedgehog signalling pathway, although many details of this process are not fully understood (see main article). In particular, it is not clear how cholesterol gains access to the Smoothened cysteine-rich domain. Cholesterol can be released from the membrane into the extracellular space by a process called desorption, but its insolubility makes this energetically unfavourable. Alternatively, a sterol-binding protein outside cells could deliver cholesterol to Smoothened.