During the last decade, molecular genetics has provided important new insights into the pathogenesis of inherited cardiomyopathies and arrhythmias. However, their extensive genetic heterogeneity means that mutation detection by classical serial molecular techniques is time-consuming, expensive, and difficult to perform in a routine clinical screening. The situation has improved dramatically with the introduction of high throughput sequencing (HTS) platforms, which allow simultaneous screening of a large number of genes. We have developed different custom high throughput sequencing approaches for mendelian cardiac disorders. We started with a 12 gene DNA resequencing array for HCM, continued with a multiplex capture array harbouring 130 genes causative of all subtypes of inherited cardiomyopathies, their phenocopies, some arrhythmias and connective tissue disorders and ended up with a custom targeted gene panel for inherited cardiomyopathies. All these approaches showed to be reliable mutation detection tools but also highlighted the complexity of variant interpretation as the most demanding challenge of HTS methods.