The study of innate immunity to bacteria has focused heavily on the mechanisms by which mammalian cells detect lipopolysaccharide (LPS), the conserved surface component of Gram-negative bacteria. While Toll-like receptor 4 (TLR4) is responsible for all the host transcriptional responses to LPS, recent discoveries have revealed the existence of several TLR4-independent responses to LPS. These discoveries not only broaden our view of the means by which mammalian cells interact with bacteria, but they also highlight new selective pressures that may have promoted the evolution of bacterial immune evasion strategies. In this review, we highlight past and recent discoveries on host LPS sensing mechanisms and discuss bacterial countermeasures that promote infection. By looking at both sides of the host-pathogen interaction equation, we hope to provide comprehensive insights into host defense mechanisms and bacterial pathogenesis.