Melusin is a protein selectively expressed in skeletal muscles and heart and highly conserved in vertebrates. Melusin is part of the heat shock protein 90 machinery and acts as molecular chaperone in controlling cardiomyocyte survival and adaptive hypertrophy signaling pathways in the heart in response to different stress conditions. The role of melusin has been extensively investigated in genetically modified mice over the past years disclosing an important cardioprotective function of this unique muscle-specific chaperone protein in different pathological conditions. This review highlights the findings in animal models and the molecular mechanisms underlying melusin cardioprotective function.