Abundant synthesis of heme during erythropoiesis is enabled by erythroid-specific genes or mRNA isoforms for the first 4 enzymatic steps in heme biosynthesis. Congenital erythropoietic porphyria (CEP) is caused by inactivating mutations in URO-synthase, the enzyme responsible for the synthesis of uroporphrynogen III. Activating mutations in ALA synthase-2 (ALAS-2) can cause X-linked erythropoietic protoporphyria or, as To-Figueras et al now show, can aggravate the clinical and laboratory phenotype of CEP. Inactivating mutations of ALAS-2 cause hereditary X-linked sideroblastic anemia. ALA indicates aminolevulinic acid; HMB, hydroxymethylbilane; URO I, uroporphrynogen I; and COPRO I, coproporphrynogen I. Professional illustration by Debra T. Dartez.