Matrix metalloproteinase 9 (MMP-9; gelatinase B) belongs to the subfamily of MMPs that play an important role in tissue remodelling in normal and pathological inflammatory processes. MMP-9 is a major secretion product of macrophages and a component of cytoplasmic granules of neutrophils. The enzyme is also secreted by lymphocytes and stromal cells upon stimulation by inflammatory cytokines, or upon delivery of bi-directional activation signals following integrin-mediated cell-cell or cell -extracellular matrix (ECM) contacts. Since the integrity of the tissue architecture is closely dependent of the delicate balance between MMPs and their inhibitors, excessive production of MMP-9 is linked to tissue damage and degenerative inflammatory disorders. As a consequence, regulation of gene transcription and tissue-specific expression of MMP-9 in normal and diseased states are being actively investigated to pave the way for new therapeutic targets. The objective of this article is to provide an overview of recent developments in the field of mmp-9 gene expression in different cell types, from the triggering of cell-surface receptors, to the activation of cytoplasmic mediators and transcription factors responsible for the activation of MMP-9 promoter. We will then focus on emerging evidence showing that transcription of mmp-9 gene can be controlled by epigenetic mechanisms. The usefulness of targeting the signalling pathways regulating MMP-9 expression for the treatment of inflammatory disorders and other indications will be discussed in light of these findings.