Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac‐specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2–5 is an important member of this group. Indeed, more than 40 heterozygous NKX2–5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2–5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2–5 mutations are one‐time detections with single‐positives or private to families. Furthermore, there is lack of genotype–phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2–5 mutations or the same NKX2–5 mutation associated with diverse malformations. Here, we summarize published NKX2–5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved. Hum Mutat 31:1–10, 2010. © 2010 Wiley‐Liss, Inc.