Cardiomyopathies and heart failure are death-threatening diseases with heterogeneous causes and modest treatment effectiveness.30-40% of which are inheritable due to hundreds of mutations in dozens of sarcomere and cytoskeleton genes.While mutations in sarcomeric proteins have been linked to various human cardiovascular diseases, it is unclear why mutations in different sarcomeric genes or different mutations in the same gene result in distinct diseases.The goal of our research is to use titin as a paradigm to investigate molecular mechanisms of sarcomere based cardiac diseases.We have identified six titin mutants in zebrafish from mutagenesis screens.By positional cloning, we demonstrated that phenotypes from one mutant allele, pikm171, resemble human dilated cardiomyopathy (DCM).We recently identified the full-length genomic sequence for zebrafish titin (ttnl) and cloned the other titin homologue (ttn2) in zebrafish.We will present our data on characterization of the diverged functions of the two titin homologues and discuss the potential of zebrafish as a genetic model for human cardiomyopathy and heart failure.The studies in this tropical fish may lead to novel therapeutic strategies for cardiomyopathy.