Using in vitro and in vivo assays, we demonstrate that ST3GAL1, a β-galactoside-α-2,3-sialyltransferase-1 that catalyzes the transfer of sialic acid from cytidine monosphosphate (CMP)-sialic acid to galactose-containing substrates, is a crucial driver of melanoma invasion and metastasis downstream the SOX2-GLI1 transcriptional complex. The gene discussed is SOX2; the disease is melanoma.