Understanding the molecular mechanisms through which the heart could be protected from ischaemic injury is of major interest and offers a potential route for the development of new therapies. Recently, several studies have uncovered intriguing relationships between nitric oxide-induced protein thiol modifications and the cardioprotected phenotype. In a highly cited, seminal article published in the Biochemical Journal in 2006, Burwell and colleagues addressed this issue and provided direct evidence for S-nitrosation of complex I of the mitochondrial electron transport chain. These authors were the first to show increased S-nitrosation of mitochondrial proteins from hearts subjected to the cardioprotective process known as ischaemic preconditioning. This study has paved the way for further investigations that collectively reveal a potential link between the mitochondrial S-nitrosoproteome and ischaemic preconditioning.