Bacteria use two-component regulatory systems (TCSs) to adapt to changes in their environment by changing their gene expression. In this study, we show that the EnvZ/OmpR TCS of the clinically relevant opportunistic pathogen Klebsiella pneumoniae plays an important role in successfully establishing lung infection and virulence. In addition, we elucidate the K. pneumoniae OmpR regulon within the host. This work suggests that K. pneumoniae OmpR might be a promising target for innovative anti-infectives.