CaMKII!, a calcium/calmodulin-dependent protein kinase, plays pivotal roles in the development of heart disease. In this issue of The Journal of Pathology , Salma Awad and colleagues demonstrate that CaMKII! is engaged in both pathological hypertrophy and heart failure. By analysis of mouse and human heart samples, they found that the level of CaMKII! is increased in both pathological processes. Further studies demonstrated that CaMKII! mediates the phosphorylation of histone H3 at serine 10 (H3S10), which then tethers the chaperone protein 14-3-3 to promoter regions of fetal cardiac genes to activate their transcription. Combined with recent highlights on transcription regulation, this study revealed a fuzzy boundary between pathological hypertrophy and subsequent heart failure and indicates that current therapeutic strategies towards heart failure may have potential risks to patients.