Bacteriophages (phages) and their bacterial hosts are abundant in all earth environments. To maintain a balance between phage and host levels in dynamic environments, phages integrate intracellular and environmental molecular signals to tune their yield. There is a direct correlation between phage yield and lysis timing. Combining genetic selections with functional assays, we have identified the molecular players that regulate lysis timing in the E. coli phage N4 and related phage infecting Gram-negative pathogens. By revealing the underlying molecular mechanisms that govern phage yield, we have uncovered handles that can be exploited to prevent, or trigger, bacterial cell lysis by phages, including during their large-scale production for therapeutics or other applications.