Septic shock is a complicated syndrome in which pro-inflammatory and anti-inflammatory processes are dynamically interconnected and regulated. Central to these processes is the monocyte, which produces large quantities of pro-inflammatory cytokines in the presence of bacterial products. During the course of sepsis, the production of compensatory anti-inflammatory mechanisms may deactivate monocytes and lead to a state of paralysis. This situation is in fact similar but not identical to that known as tolerance, in which normal monocytes prechallenged with lipopolysaccharide do not respond to a second challenge of lipopolysaccharide. Here, we review some of the cellular mechanisms that may lead to monocyte deactivation and discuss the clinical implications they may have.