The Z-disc has traditionally been viewed as a structure required to maintain sarcomeric function and integrity. More recently, the sarcomeric Z-disc has also emerged as a nodal point in cardiomyocyte signaling and mechanotransduction. This notion is not only supported by several transgenic animal models, but also by the identification of mutations in various Z-disc proteins, resulting in dilated or hypertrophic cardiomyopathy in patients. This review will thus focus on the role of the sarcomeric Z-disc and its associated proteins in the pathogenesis of cardiomyopathy.