ActinoGEN is an integrated project aimed at developing novel genomics-based approaches to exploit hitherto overlooked genetic resources for new antibiotics. Drug discovery will focus on (1) accessing new antibiotic biosynthetic pathways from diverse actinomycetes that have yet to be cultured, (2) activating cryptic pathways from well-characterised actinomycetes, and (3) engineering novel hybrid antibiotics by combinatorial biosynthesis. To greatly accelerate the drug discovery process, a parallel strategy will be to engineer generic hosts optimised to produce high antibiotic yields. With the complete genome sequence of the model actinomycete, Streptomyces coelicolor, and mobilization of a pan-European effort to apply newly developed multidisciplinary post-genomic technologies, a holistic understanding of the physiology and regulation of antibiotic biosynthesis is achievable for the first time. This will, in turn, permit rational intervention to engineer generic hosts for high-yield antibiotic production. This synergy of discovery linked to overproduction will place the European biotechnology sector at the forefront of developing much-needed new antibiotics to combat multi-drug resistant pathogens.