In nearly all bacterial species examined so far,
amino acid starvation triggers the rapid accumulation of the
nucleotide second messenger (
p)ppGpp, the effector of the stringent response. While for years the
enzymes involved in (
p)ppGpp metabolism and the significance of (
p)ppGpp accumulation to stress survival were considered well defined, a recent surge of interest in the field has uncovered an unanticipated level of diversity in how bacteria metabolize and utilize (
p)ppGpp to rapidly synchronize a variety of biological processes important for growth and stress survival. In addition to the classic activation of the stringent response, it has become evident that (
p)ppGpp exerts differential effects on cell physiology in an incremental manner rather than simply acting as a biphasic switch that controls growth or stasis. Of particular interest is the intimate relationship of (
p)ppGpp with persister cell formation and virulence, which has spurred the pursuit of (
p)ppGpp inhibitors as a means to control recalcitrant
infections. Here, we present an overview of the
enzymes responsible for (
p)ppGpp metabolism, elaborate on the intricacies that link basal production of (
p)ppGpp to bacterial homeostasis, and discuss the implications of targeting (
p)ppGpp synthesis as a means to disrupt long-term bacterial survival strategies.