s Hypoplastic left heart syndrome (HLHS) is a rare and severe defect in which the structures of the left side of the heart are severely underdeveloped. Only a very small minority of HLHS cases can currently be explained. This review summarizes how growth of the left-sided structures of the heart is initiated very early during development and which mechanisms could be defective in HLHS. Numerous cascades driving development of ventricular cardiomyocytes have been described and are put into perspective. Current genetic, epigenetic, and hemodynamic concepts in HLHS pathogenesis are discussed in the context of both animal and human models of impaired growth of left-sided structures of the heart. Understanding the contribution of these factors may be crucial for stratification of therapeutic interventions in HLHS.