Bacterial pathogens can be very efficient at causing disease and are the cause of some of the worst epidemics that have affected humanity. However, most infections are prevented by the actions of our immune system. Immune activation depends on the rapid detection of bacteria by a diverse family of sensory proteins known as pattern recognition receptors. These receptors detect conserved features of bacteria that are not found in humans but are often necessary for survival within the host or environment. In this review, we discuss the strategies used by pattern recognition receptors to detect bacteria and their products. We also discuss emerging evidence that some pattern recognition receptors can be activated by bacterial pathogens specifically, through the surveillance of host activities that are commonly targeted by virulence factors. This collection of surveillance mechanisms provides an interconnected network of defense, which is important to maintain the germ-free environment of the inner organs of humans and other multicellular organisms.