The serine proteases cathepsin G, human leukocyte elastase and proteinase 3 are major contents of neutrophil granulocytes and are released at sites of inflammation. Although the traditional function of neutrophil-derived antimicrobial proteases is to ingest and kill bacteria, recent studies provided evidence that these proteases are able to activate specifically pro-inflammatory cytokines including interleukin-1 beta and TNF-alpha and lead to the activation of different receptors including epidermal growth factor receptor and proteinase-activated receptors. Neutrophil serine proteases might therefore be important regulators of the inflammatory innate immune response and are interesting targets for new therapeutic approaches against inflammatory disorders. This review summarizes the current knowledge on the molecular regulation of the innate immune response by neutrophil-derived serine proteases.