Streptomyces, the main antibiotic-producing bacteria, responds to changing environmental conditions through a complex sensing mechanism and two-component systems (TCSs) play a crucial role in this extraordinary "sensing" device.Moreover, TCSs are involved in the biosynthetic control of a wide range of secondary metabolites, among them commercial antibiotics. Increased knowledge about TCSs can be a powerful asset in the manipulation of bacteria through genetic engineering with a view to obtaining higher efficiencies in secondary metabolite production. In this review we summarise the available information about Streptomyces TCSs, focusing specifically on their connections to antibiotic production.