Purpose of Review <p>Despite surgical and medical advances, congenital heart disease (CHD) remains a significant cause of morbidity and mortality in children and adults. The molecular mechanisms underlying cardiac injury in this population are still being defined. This review summarizes current literature investigating the molecular pathways involved in cardiac injury associated with CHD.</p> Recent Findings <p>Studies have highlighted the drivers of cardiac injury as well as dysregulated signaling pathways, metabolic dysfunction, and altered gene expression profiles in the progression of cardiac injury in CHD. Advances in transcriptomics and metabolomics have provided deeper insight into cell-specific responses and have uncovered novel molecular drivers of disease progression.</p> Summary <p>Understanding the molecular landscape of cardiac injury in CHD is critical for the development of improved diagnostic tools and targeted therapies. Continued integration of multi-omics and clinical studies will be essential to translating these discoveries into effective treatments for patients with CHD.</p> Opinion Statement <p>Congenital heart disease (CHD) is an umbrella term for complex and heterogenous groups of structural heart diseases. From conotruncal defects to single ventricle physiologies, each of these structural disorders occur due to unique developmental disruptions and carry distinct risks for cardiac stress, injury, and remodeling. Over the course of the last few decades, significant improvements in medical and surgical care have improved outcomes in CHD. Nonetheless, the heterogenous nature of these disorders and broad circumstances for cardiac injury, from anything like chronic volume overload to ischemia reperfusion injury, lead to high morbidity and mortality in this population. A remarkable challenge in the field is the lack of studies characterizing models of cardiac injury in CHD and hence, the lack of evidence-based therapies to improve outcomes. Further, grouping heterogenous CHD subtypes to increase power in studies is a common approach which limits our ability to identify generalizable molecular processes seen in CHD lesions. With movement towards a precision medicine approach, integration of high throughput sequencing approaches, like single nucleus RNA sequencing, gives us the ability to dissect the microtissue environment in each CHD subtype at high resolution. This allows us to build a true mechanistic understanding of CHD by subtype and to decipher the mechanisms of cardiac injury, while also identifying novel therapeutic targets to tailor future interventions.</p>