Production of red blood cells (erythropoiesis) in the vertebrate embryo is critical to its survival and subsequent development. As red cells are the first blood cells to appear in embryogenesis, their origin reflects commitment of mesoderm to an hematopoietic fate and provides an avenue by which to examine the development of the hematopoietic system, including the hematopoietic stem cell (HSC). We discuss the genetics of erythropoiesis as studied in two systems: the mouse and zebrafish (Danio rerio). In the mouse, targeted disruption has established several genes as essential at different stages of hematopoiesis or erythroid precursor cell maturation. In the zebrafish, numerous mutants displaying a wide range of phenotypes have been isolated, although the affected genes are unknown. In comparing mouse knockout and zebrafish mutant phenotypes, we propose a pathway for erythropoiesis that emphasizes the apparent similarity of the mutants and the complementary nature of investigation in the two species. We speculate that further genetic studies in mouse and zebrafish will identify the majority of essential genes and define a regulatory network for hematopoiesis in vertebrates.