Congenital Heart Disease (CHD) affects 6-8 per 1000 live births. It is the most common cause of death in newborn infants and is a significant burden on society with an increasing adult population. A number of genes have been implicated in disease development; however traditional research techniques such as linkage analysis are generally not suited as they require large families with multiple affected individuals which are rare in CHD. While more recent techniques, such as GWAS, provide insight into population-attributable risks, the information cannot be directly related to the affected individual. In comparison, the information gained from next generation sequencing (NGS) technology can directly impact the treatment and care of patients and their families. For this reason NGS is rapidly becoming the analysis of choice in both clinical and research arenas. The different types of NGS techniques have unique sets of advantages and disadvantages and it is important to assess these in the context of the disease characteristics, as well as the purpose of the analysis, so that the most appropriate technology is selected. Based on our experience and recent findings from research in CHD, we propose that a gene panel-based approach is currently more suited to clinical workflow and the molecular analysis of CHD and that exome sequencing and whole genome sequencing are best suited to a research environment that can provide the necessary support and analyses required for novel gene discovery.