Heme oxygenase (HO) catalyzes the oxygen-dependent cleavage of heme to produce biliverdin IXα in phycobilin biosynthesis. In the genome of the cyanobacterium Synechocystis sp. PCC 6803 there are two genes, ho1 (sll1184) and ho2 (sll1875), encoding HO isoforms. Reverse transcription-PCR indicated that ho1 is constitutively expressed, and ho2 is induced under micro-oxic conditions. A mutant lacking ho1 (Δho1) failed to grow under aerobic conditions while it did grow at a significantly slower rate than the wild type under anaerobic (micro-oxic) conditions. When micro-oxically grown Δho1 was incubated under aerobic conditions, the cells underwent chlorosis with a significant decrease in phycocyanin accompanied by anomalous accumulation of protoporphyrin IX. These results suggested that HO1 is essential for aerobic growth as the sole HO and is dispensable under micro-oxic conditions. A mutant lacking ho2 (Δho2) grew under both aerobic and micro-oxic conditions like the wild type at low light intensity (50 μmol(photon) m⁻² s⁻¹). At higher light intensity (120 μmol(photon) m⁻² s⁻¹) the Δho2 mutant showed significant growth retardation under micro-oxic conditions. It is suggested that HO2 operates as a dominant HO under high light and micro-oxic environments and acts as an accessory HO at low light intensity. Constitutive expression of HO2 in a neutral site of the chromosome restored aerobic growth of Δho1, suggesting that HO2 has an activity high enough to substitute for HO1 under aerobic conditions. The differential operation of two isoforms/enzymes in cyanobacterial tetrapyrrole biosynthesis to adapt to low oxygen environments is discussed, including three other reactions.