This study revisits the cellular composition of the heart to better understand changes during pathogenesis and to inform tissue engineering and regeneration strategies. Using genetic tools and cellular markers, the authors examined the relative frequencies of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in both mouse and human hearts. Immunohistochemistry revealed that endothelial cells constitute over 60%, hematopoietic-derived cells 5–10%, and fibroblasts under 20% of the non-myocytes in the heart. Flow cytometry and high-dimensional analysis confirmed that endothelial cells are the most abundant cell type, while fibroblast numbers are smaller than previously estimated. The study also describes an alternative surface marker for identifying resident cardiac fibroblasts. These findings redefine the cellular composition of the heart, highlighting the significant role of endothelial cells in cardiac function and response to injury.This study revisits the cellular composition of the heart to better understand changes during pathogenesis and to inform tissue engineering and regeneration strategies. Using genetic tools and cellular markers, the authors examined the relative frequencies of cardiac endothelial cells, hematopoietic-derived cells, and fibroblasts in both mouse and human hearts. Immunohistochemistry revealed that endothelial cells constitute over 60%, hematopoietic-derived cells 5–10%, and fibroblasts under 20% of the non-myocytes in the heart. Flow cytometry and high-dimensional analysis confirmed that endothelial cells are the most abundant cell type, while fibroblast numbers are smaller than previously estimated. The study also describes an alternative surface marker for identifying resident cardiac fibroblasts. These findings redefine the cellular composition of the heart, highlighting the significant role of endothelial cells in cardiac function and response to injury.