This minireview by John J. Mekalanos discusses the sophisticated signal transduction systems that control the coordinated expression of virulence determinants in bacteria. The author highlights the importance of environmental cues, such as host products, temperature, osmolarity, calcium, and stress, in regulating virulence gene expression. These cues are often used by pathogens to coordinate the expression of multiple virulence factors, which are essential for successful infection and survival within host tissues. The review also explores the regulatory strategies employed by bacteria, including "no harm, no foul," "intentional foul," "transition game," "full-court press," and "four corners," to balance virulence and host immune response. Understanding these regulatory mechanisms is crucial for developing strategies to combat bacterial infections.This minireview by John J. Mekalanos discusses the sophisticated signal transduction systems that control the coordinated expression of virulence determinants in bacteria. The author highlights the importance of environmental cues, such as host products, temperature, osmolarity, calcium, and stress, in regulating virulence gene expression. These cues are often used by pathogens to coordinate the expression of multiple virulence factors, which are essential for successful infection and survival within host tissues. The review also explores the regulatory strategies employed by bacteria, including "no harm, no foul," "intentional foul," "transition game," "full-court press," and "four corners," to balance virulence and host immune response. Understanding these regulatory mechanisms is crucial for developing strategies to combat bacterial infections.