O-linked glycans on plasma membrane proteins are altered in cancer cells, leading to changes in cell adhesive properties and contributing to metastasis. Mechanisms of how these carbohydrates alter tumor spread remain vague. In this issue of Cancer Discovery, Murugaesu and colleagues, using an in vivo functional RNA interference metastasis screen, identified sialyltransferase ST6GalNAc2 as a novel metastasis suppressor gene. Aggressive estrogen receptor-negative breast cancers with reduced ST6GalNAc2 expression alter O-linked glycans on tumor cell surface, increasing soluble lectin galectin-3 binding and tumor cell clustering at metastatic sites.