Wnt ligands are lipid-modified molecules that are acylated in the endoplasmic reticulum of secretory cells with monounsaturated palmitoleic acid (16:1). SCD1, and possibly SCD5, mediates the desaturation of palmitic to palmitoleic acid, providing the substrate for the O-acyl-transferase Porcupine (Porcn) that acylates Wnt ligands. The acylation is critical for Wnt release from secretory cells (left) by the cargo receptor Wls (Wntless), and for inducing signaling activity upon binding to receptors in the target cell (right). While a role of SCD1 in Wnt3a synthesis and signaling has been established, SCD5 could also participate in the mechanisms of synthesis and signaling of Wnt ligands, including Wnt5a. HSPG: Heparan sulfate proteoglycan; ROR2: Receptor tyrosine kinase like orphan receptor 2; FZD: frizzled class receptor; LRP5/LRP6 LDL receptor related protein 6/ protein 5.