Estimates of gene-essentiality inferred from expression and network topology discriminate key regulators of erythropoiesis. Erythroid lineage-specific estimates of ranked gene-essentiality were made for each transcription factor expressed in the erythropoiesis expression dataset. The distribution of scores in all three erythropoietic lineages (A: adult definitive; B: fetal definitive; C: primitive) are strongly right skewed. Known definitive regulators (indicated by black dots and stars) exhibit a bi-modal distribution, with essential and key regulators, including Klf1, Gata1 and Tal1 (black stars), falling in the right tail and non-essential factors (e.g., Nfia) falling near the distribution mode. Thus, right-tail genes in all distributions (S ≥1.8) most likely possess topological and expression properties most similar to those of the known essential regulators of adult definitive erythropoiesis.