Contemporary DNA sequencing approaches are increasingly used as diagnostic tools within clinical medicine, driven by rapid reductions in cost and improvements in speed. In 2014, Illumina, Inc. launched a system that could sequence an entire human genome for under $1000,1 with sequencing and analysis achievable in under 2 days.2,3 For inherited disease, next-generation sequencing (NGS) technologies have been applied in 3 broad categories: (1) gene panels, where a collection of predefined genes for a given condition, or a group of closely related conditions, are sequenced; (2) whole-exome sequencing (WES), where the majority of the protein-coding portions of the genome (≈2% of the genome) is sequenced; and (3) whole-genome sequencing (WGS), where the majority of the genome is sequenced, including nonprotein-coding DNA. In the management of inherited cardiovascular disease, there has been increasing use of genetic testing as major healthcare systems establish centers of excellence. In most cases, these tests now feature NGS approaches. However, as we transition from traditional to NGS approaches, it is important that noninferiority with traditional practices is firmly established. Furthermore, our ability to correctly interpret the clinical impact of variants derived from these sequencing efforts remains suboptimal. The recent analysis and public release of sequence data from tens of thousands of individuals established that rare variation is common in humans, meaning that only a small proportion of rare variants will actually be causal of rare genetic disease. Indeed, even when rare variants emerge that could potentially explain a given presentation, the classification of such variants is often discordant between laboratories. Here, we will explore the challenge and opportunity of NGS for inherited cardiovascular disease. First, we describe recent advances in sequencing and interpretation facilitated by large-scale population genomics studies. Next, we outline current approaches to clinical genetic testing and describe areas of …