gamma-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. The cleavage of substrates by gamma-secretase plays diverse biological roles in producing essential products for the organism. More than 90 transmembrane proteins have been reported to be substrates of gamma-secretase. Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-beta (Abeta) and the Notch intracellular domain (NICD), respectively. The wide spectrum of gamma-secretase substrates has made analyses of the pathology of gamma-secretase-related diseases and underlying mechanisms challenging. Inflammation is an important aspect of disease pathology that requires an in-depth analysis. gamma-Secretase may contribute to disease development or progression by directly increasing and regulating production of pro-inflammatory cytokines. This review summarizes recent evidence for a role of gamma-secretase in inflammatory diseases, and discusses the potential use of gamma-secretase inhibitors as an effective future treatment option.