Difficult-to-treat chronic and recurrent bacterial infections are often caused by bacteria that are sensitive to commonly used antibiotics. One reason for this recalcitrance is that bacteria can enter a state of low metabolic activity called persistence in which they are tolerant to otherwise deadly assaults, including antibiotics. Our work is focusing on the pivotal role of the general bacterial stress response, known as “the stringent response” in this phenomenon. Indeed, stochastic variation of the stringent response regulator (p)ppGpp triggers persister cells formation in Escherichia coli. However, the molecular mechanisms by which environmental cues activate the stringent response are still largely unknown and represent one of the most fundamental, unsolved problems in prokaryotic molecular biology. Moreover the stringent response is also required for virulence of almost all bacterial pathogens, strongly arguing that novel insights into (p)ppGpp biology will lead to novel methods to combat infections. Our objectives are to better understand the molecular mechanisms regulating the activity of the enzymes responsible for synthesis and degradation of (p)ppGpp with special emphasis on their role in bacterial persistence.