Onset of the biosynthesis of bioactive secondary metabolites in batch cultures of actinomycetes occurs after the rapid growth phase, following a transition phase which involves complex metabolic changes. This transition is triggered by nutrient starvation or by other environmental stress signals. Expression of genes encoding bioactive secondary metabolites is governed by cascades of pathway specific regulators and networks of cross-talking global regulators. Pathway specific regulators such as Streptomyces antibiotic regulatory proteins, LAL-type and LysR-type regulators respond to autoregulatory proteins that act in concert with their cognate ligands (e.g. γ-butyrolactone receptor proteins and their cognate γ-butyrolactone ligands). Global regulators such as PhoR-PhoP and other two component systems and orphan response regulators, such as GlnR, control set of genes affecting primary and secondary metabolism. GlnR and, therefore, nitrogen metabolism genes are under phosphate control exerted by binding of PhoP to PHO boxes located in the promoter region of GlnR. A few pleiotropic regulatory genes, such as areB (ndgR), dmdR1 or dasR connect primary metabolism (amino acid biosynthesis, N-acetylglucosamine or iron levels) with antibiotic biosynthesis. Some atypical response regulators that require specific small ligands appear to be involved in feedback control of antibiotic production. All these mechanisms together modulate, in a coordinated manner, different aspects of Streptomyces metabolism as a real "protection net" that prevents drastic changes in metabolism that may be deleterious for cell survival.