Hypoplastic left heart syndrome (HLHS) is a complex congenital heart disease (CHD) involving hypoplasia of the left ventricle (LV), aorta (Ao), and mitral valve. HLHS was uniformly fatal in the past, now survivable with 3-stage surgical palliation. However, there is high morbidity and mortality, with 25% of HLHS patients either dying or having a heart transplant within 1 year of age. The causes for such high morbidity and mortality are not well understood, but the majority of deaths are directly or indirectly related to cardiovascular/hemodynamics causes. Studies in a mouse model of HLHS uncover important contributing factors for single-ventricle patients such as the patient’s intrinsic factors related to mitochondrial dysfunction, and derangements in the early stages of embryonic development. The HLHS mutant mice were noted to have metabolic dysfunction accompanied by cell cycle arrest and cardiomyocyte differentiation defects. Intrinsic cell defects may contribute to cardiac failure in the HLHS population. Moreover, strong evidence of the genetic etiology of HLHS has come from the observation that HLHS has a high recurrence risk and is associated with various chromosomal abnormalities. In this chapter, we will review the basic pathophysiology, pertinent pre-and post-operative managements of HLHS and recent advances derived from the HLHS mouse model.