Two-component and phosphorelay signal-transduction systems of pathogenic bacteria control the expression of genes encoding virulence factors and essential functions. Recent systematic gene inactivation studies have confirmed the integral role of two-component systems in the pathogenesis of diseases caused by several microorganisms and highlighted the validity of using these systems as targets for therapeutic intervention. Structural studies of signal-transduction proteins have recently revealed common features that may allow rational drug design for therapeutic intervention. In particular, the conserved domains of response regulators may represent the best targets for inhibition.