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The cues governing cardiac cell-fate decisions, cardiac differentiation, and three-dimensional morphogenesis are rapidly being elucidated. Several themes are emerging that are relevant for childhood and adult heart disease and the growing field of stem cell biology. This review will consider our current understanding of cardiac cell-fate determination and cardiogenesis—largely derived from developmental studies in model organisms and human genetic approaches—and examine future implications for diagnosis, prevention, and treatment of heart disease in the young and old.