As part of a comprehensive postgenomic investigation of the model archaeon Halobacterium sp. strain NRC-1, we used whole-genome DNA microarrays to compare transcriptional profiles of cells grown under anaerobic or aerobic conditions. When anaerobic growth supported by arginine fermentation was compared to aerobic growth, genes for arginine fermentation (arc) and anaerobic respiration (dms), using trimethylamine N-oxide (TMAO) as the terminal electron acceptor, were highly upregulated, as was the bop gene, required for phototrophic growth. When arginine fermentation was compared to anaerobic respiration with TMAO, the arc and dms genes were both induced with arginine, while TMAO induced the bop gene and major gas vesicle protein (gvpAC) genes specifying buoyant gas vesicles. Anaerobic conditions with either TMAO or arginine also upregulated the cba genes, encoding one of three cytochrome oxidases. In-frame deletion of two COG3413 family regulatory genes, bat and dmsR, showed downregulation of the bop gene cluster and loss of purple membrane synthesis and downregulation of the dms operon and loss of anaerobic respiration capability, respectively. Bioinformatic analysis identified additional regulatory and sensor genes that are likely involved in the full range of cellular responses to oxygen limitation. Our results show that the Halobacterium sp. has evolved a carefully orchestrated set of responses to oxygen limitation. As conditions become more reducing, cells progressively increase buoyancy, as well as capabilities for phototrophy, scavenging of molecular oxygen, anaerobic respiration, and fermentation.