Wnt proteins are critical regulators of signaling networks during embryonic development and in adult tissue homeostasis. The generation of active Wnt proteins requires their regulated secretion into the extracellular space. Once secreted, Wnts signal through the cell surface via receptor binding on Wnt-receiving cells, a mechanism that is prevalent in stem cell and cancer biology. Important to both Wnt secretion and receptor recognition is their post-translational fatty acylation. In this Perspective, we highlight progress in elucidating the biochemistry of Wnt fatty acylation and provide a molecular view on the enzymology of substrate recognition and catalysis, with a focus on the Wnt O-acyltransferase porcupine. Special emphasis is given to Wnt fatty acid biosynthesis, Wnt-porcupine interactions, clinical mutations of porcupine and emerging therapeutics for perturbing Wnt fatty acylation in cancer. Finally, we discuss models for the functional role of the unsaturated fatty acyl chain in mediating lipid-protein interactions and in Wnt trafficking.