Members of the soil-dwelling prokaryotic genus Streptomyces are indispensable for the recycling of complex polysaccharides, and produce a wide range of natural products. Nutrient availability is a major determinant for the switch to development and antibiotic production in streptomycetes. Carbon catabolite repression (CCR), a main signaling pathway underlying this phenomenon, was so far considered fully dependent on the glycolytic enzyme glucose kinase (Glk). Here we provide evidence of a novel Glk-independent pathway in Streptomyces coelicolor, using advanced proteomics that allowed the comparison of the expression of some 2,000 proteins, including virtually all enzymes for central metabolism. While CCR and inducer exclusion of enzymes for primary and secondary metabolism and precursor supply for natural products is mostly mediated via Glk, enzymes for the urea cycle, as well as for biosynthesis of the γ-butyrolactone Scb1 and the responsive cryptic polyketide Cpk are subject to Glk-independent CCR. Deletion of glkA led to strong downregulation of biosynthetic proteins for prodigionin and calcium-dependent antibiotic (CDA) in mannitol-grown cultures. Repression of bldB, bldN, and its target bldM explains the poor development of S. coelicolor on solid-grown cultures containing glucose. A new model for carbon catabolite repression in streptomycetes is presented.