Pathogenic bacteria produce a variety of effectors and/or toxins, which subvert target cell/tissue functions in the infected hosts. Some of those effectors/toxins also perturb host defense mechanism, thereby making up more complicated pathophysiological conditions. Such bacterial effectors/toxins may have been positively selected during evolution because they directly strike vulnerable points in the host system. In turn, this indicates that systemic exploration of molecules and signaling pathways targeted by bacterial effectors/toxins provides a powerful tool in digging up an unexpected Achilles' heel(s), malfunctioning of which gives rise to disorders not restricted to infectious diseases. Based on this viewpoint, this review shows molecular basis underlying host susceptibility and vulnerability to diseases through the studies of host molecules targeted by bacterial effectors and toxins.