An aortic valve typically consists of three valve leaflets, named after their orientation relative to the left and right coronary artery. In 0.5–2 % of the general population, the aortic valve comprises only two leaflets, which is termed a bicuspid aortic valve (BAV). BAV is believed to result from abnormal embryological fusion of two adjacent cusps, due to defective epithelial-to-mesenchymal transition in the outflow tract or abnormal activity of cardiac neural crest cells. Although intrinsically largely asymptomatic, it associates with severe cardiovascular complications such as aortic coarctation and thoracic aortic aneurysms and dissections. In the past, these manifestations accounted for a higher mortality and morbidity than all other congenital heart defects combined. As to significant advances in perioperative management, however, survival rates between BAV and tricuspid aortic valve individuals have now almost equaled. Further improvement of the existing interventions as well as discovery of novel therapeutic targets and accurate predictive biomarkers for BAV-related complications is still warranted though. Therefore, the condition’s pathomechanisms are currently being extensively investigated. Although these investigations have been insightful to some extent, knowledge gaps have increasingly been exposed, highlighting the importance of future experiments digging into the etiology of BAV. In this chapter, a comprehensive overview on the clinical and yet unraveled molecular characteristics of BAV will be provided, as well as a reflection on the factors underlying its current etiological inscrutability.