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Streptomycetes are well-known producers of numerous bioactive secondary metabolites widely used in medicine, agriculture, and veterinary. Usually, their genomes encode 20–30 clusters for the biosynthesis of natural products. Generally, the onset and production of these compounds are tightly coordinated at multiple regulatory levels, including cluster-situated transcriptional factors. Rishirilides are biologically active type II polyketides produced by <i>Streptomyces bottropensis</i>. The complex regulation of rishirilides biosynthesis includes the interplay of four regulatory proteins encoded by the <i>rsl</i>-gene cluster: three SARP family regulators (RslR1-R3) and one MarR-type transcriptional factor (RslR4). In this work, employing gene deletion and overexpression experiments we revealed RslR1-R3 to be positive regulators of the biosynthetic pathway. Additionally, transcriptional analysis indicated that <i>rslR2</i> is regulated by RslR1 and RslR3. Furthermore, RslR3 directly activates the transcription of <i>rslR2</i>, which stems from binding of RslR3 to the <i>rslR2</i> promoter. Genetic and biochemical analyses demonstrated that RslR4 represses the transcription of the MFS transporter <i>rslT4</i> and of its own gene. Moreover, DNA-binding affinity of RslR4 is strictly controlled by specific interaction with rishirilides and some of their biosynthetic precursors. Altogether, our findings revealed the intricate regulatory network of teamworking cluster-situated regulators governing the biosynthesis of rishirilides and strain self-immunity.