Tumor necrosis factor (TNF) tolerance in monocytes and macrophages means that preexposure to TNF reduces the sensitivity in these cells to a subsequent restimulation with this cytokine. Differential effects arise following preincubation with both low and high doses of TNF resulting in absolute as well as induction tolerance affecting specific immunologically relevant gene sets. In this review article, we summarize the relevance of TNF tolerance in vivo and the molecular mechanisms underlying these forms of tolerance including the role of transcription factors and signaling systems. In addition, the characteristics of cross-tolerance between TNF and lipopolysaccharide (LPS) as well as pathophysiological aspects of TNF tolerance are discussed. We conclude that TNF tolerance may represent a protective mechanism involved in the termination of inflammation and preventing excessive or prolonged inflammation. Otherwise, tolerance may also be a trigger of immune paralysis thus contributing to severe inflammatory diseases such as sepsis. An improved understanding of TNF tolerance will presumably facilitate the implementation of diagnostic or therapeutic approaches to more precisely assess and treat inflammation-related diseases.