Congenital heart disease (CHD) is the most common type of birth defect and affects almost 1% of the general population. Compared to other rare congenital disorders, CHD rarely shows strictly Mendelian inheritance patterns. Human genetic studies have revealed that multiple genes contribute to the disease in pathways, which affect early cardiac development. Despite recent large-scale efforts to identify causal genes for CHD, the majority of cases remain enigmatic. The challenges in identifying genotype–phenotype relationships in CHD suggest a more complex pattern of inheritance, where structural as well as single nucleotide variants contribute to the disease and modifiers tune the spectrum of cardiac malformations expressed. Here, we review the current state of genetic research in CHD and discuss the challenges in moving variant identification in CHD into the personal genomics era. Key Concepts Key Concepts * Congenital heart disease (CHD) is a complex developmental phenotype with many genes contributing to its etiology. * Single nucleotide polymorphisms (SNPs) as well as structural variants contribute to the burden of CHD in the population. * Loss of function variants (LOF) and missense mutations can have different impacts during cardiac development, thus leading to different CHD phenotypes. * Genetic factors for congenital heart malformations can be inherited autosomal recessive, autosomal dominant, X-linked or show non-Mendelian patterns in families. * Genetic background can alter the manifestation of CHD and lead to different CHD subtypes or buffer against disease.