Cardiac hypertrophy is initially an adaptive response that allows the heart to maintain cardiac output in response to an increase in haemodynamic load such as hypertension and valve diseases. However, under chronic stimulus, hypertrophy eventually becomes maladaptive and leads to heart failure. AMP-activated protein kinase (AMPK), a ubiquitously expressed stress protein kinase, has been shown to control hypertrophy, its pharmacological activation preventing the development of the disease. In line, our lab recently demonstrated that the main element explaining the anti-hypertrophic action of AMPK is linked to protein O-GlcNAcylation. O-GlcNAcylation is a post-translational modification resulting from a particular glucose metabolic pathway called the hexosamine biosynthesis pathway that leads to the transfer of UDP-N-Acetylglucosamine (GlcNac) on serine and threonine residues. We demonstrated that an increase in O-GlcNAcylation rapidly occurs during hypertrophy development and that its inhibition is sufficient to block the progression of the disease. The present talk will summarize the last findings in the domain. A particular focus will be done on the identification of the O-GlcNAcylated proteins that could be play a role in the disease development.