Mechanisms of the regulation of gene expression in prokaryotes are diverse. However, there are many similarities between the two prokaryotic domains, archaea and bacteria. Bacterial gene regulation occurs primarily at the transcription level, with posttranscriptional regulation playing secondary and context-specific roles. Even in transcriptional regulation, the focus is on the transcription initiation step. The transcription initiation rate is primarily influenced by the transcription factors that bind proximal to the promoter and regulate transcription initiation. The folded bacterial chromosome’s three-dimensional structure and the nucleoid-associated proteins play significant roles in regulating the transcription initiation. A relatively new phenomenon, riboswitches play an important role in sensing many metabolites and mediating their effect on gene expression through regulation of transcription and translation. In many bacteria, small RNAs and RNA degradation are important mechanisms of posttranscriptional regulation. Less is known about regulation in the archaeal domain. Their repertoire of transcription factors is similar to that of bacteria, and at least some regulatory mechanisms of transcription initiation have similarities.