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ALAS initiates heme synthesis by combining glycine and succinyl-CoA to form δ-aminolevulinic acid. ALAS1 is regulated largely by heme feedback and hepatic metabolic demand: heme can reduce its expression and mitochondrial import, while increased cytochrome P450 demand can raise ALAS1 expression. Glucose loading suppresses hepatic ALAS1, whereas fasting and glucagon can promote its transcription. ALAS2 regulation is linked to erythropoiesis and iron availability; iron permits translation through its mRNA iron-responsive element, while erythropoietin and hypoxia-inducible factors increase transcription. Vitamin B6 is required for ALAS activity, and substrate availability, inhibitors, and defects elsewhere in the pathway can also affect heme output. These mechanisms help explain how altered regulation contributes to porphyria and other disturbances in heme synthesis.