Natriuretic peptides (NPs) are hormones involved in maintaining heart health that undergo proteolytic cleavage to become activated. Previous work has shown that O-GalNAc glycans affect their processing and activation. Here, Goetze, Schjoldager, and colleagues now provide comprehensive characterization of O-glycosylation of NPs, revealing that all members of the NP family can be modified by O-GalNAc glycans. Intriguingly, the study discovers glycans in the receptor-binding region of the A-type natriuretic peptide (ANP), demonstrating that they affect both stability and activity of ANP. These results may inform future therapeutic approaches for heart failure using peptide glycoforms.