To investigate the molecular mechanisms that interplay between oxygen metabolism and secondary metabolism in Streptomyces natalensis, we compared the transcriptomes of the strains CAM.02 (Delta sodF), pimaricin under-producer phenotype, and CAM.04 (Delta ahpCD), pimaricin over-producer phenotype, with that of the wild type at late exponential and stationary growth phases. Microarray data interpretation was supported by characterization of the mutant strains regarding enzymatic activities, phosphate uptake, oxygen consumption and pimaricin production. Both mutant strains presented a delay in the transcription activation of the PhoRP system and pimaricin biosynthetic gene cluster that correlated with the delayed inorganic phosphate (Pi) depletion in the medium and late onset of pimaricin production, respectively. The carbon flux of both mutants was also altered: a re-direction from glycolysis to the pentose phosphate pathway (PPP) in early exponential phase followed by a transcriptional activation of both pathways in subsequent growth phases was observed. Mutant behavior diverged at the respiratory chain/tricarboxylic acid cycle (TCA) and the branched chain amino acid (BCAA) metabolism. CAM.02 (Delta sodF) presented an impaired TCA cycle and an inhibition of the BCAA biosynthesis and degradation pathways. Conversely, CAM.04 (Delta ahpCD) presented a global activation of BCAA metabolism. The results highlight the cellular NADPH/NADH ratio and the availability of biosynthetic precursors via the BCAA metabolism as the main pimaricin biosynthetic bottlenecks under oxidative stress conditions. Furthermore, new evidences are provided regarding a crosstalk between phosphate metabolism and oxidative stress in Streptomyces.