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Monensin, produced by <i>Streptomyces cinnamonensis</i>, is a polyether ionophore antibiotic widely used as a coccidiostat and a growth-promoting agent in agricultural industry. In this study, cyclic AMP receptor protein (Crp), the global transcription factor for regulation of monensin biosynthesis, was deciphered. The overexpression and antisense RNA silencing of <i>crp</i> revealed that Crp plays a positive role in monensin biosynthesis. RNA sequencing analysis indicated that Crp exhibited extensive regulatory effects on genes involved in both primary metabolic pathways and the monensin biosynthetic gene cluster (<i>mon</i>). The primary metabolic genes, including <i>acs</i>, <i>pckA</i>, <i>accB</i>, <i>acdH</i>, <i>atoB</i>, <i>mutB</i>, <i>epi</i> and <i>ccr</i>, which are pivotal in the biosynthesis of monensin precursors malonyl-CoA, methylmalonyl-CoA and ethylmalonyl-CoA, are transcriptionally upregulated by Crp. Furthermore, Crp upregulates the expression of most <i>mon</i> genes, including all PKS genes (<i>monAI</i> to <i>monAVIII</i>), tailoring genes (<i>monBI</i>-<i>monBII-monCI</i>, <i>monD</i> and <i>monAX</i>) and a pathway-specific regulatory gene (<i>monRI</i>). Enhanced precursor supply and the upregulated expression of <i>mon</i> cluser by Crp would allow the higher production of monensin in <i>S. cinnamonensis.</i> This study gives a more comprehensive understanding of the global regulator Crp and extends the knowledge of Crp regulatory mechanism in <i>Streptomyces</i>.