Reactive oxygen species (ROS) participate in an array of biological processes, including normal cell growth, oxidant signalling and cell death [1]. Monoamine oxidase (MAO) is thought to be an important contributor to increased steady state concentrations of ROS within both the mitochondrial matrix and the cytosol [2]. MAO activity can yield the formation of oxygen radicals, hydroxyl radicals, and hydrogen peroxide [3]. Many protein targets are thought to respond to intra- and extra-cellular signals by altering their primary function as catalysts to become important mediators in biological events such as cell death by utilising their oxidative capacity [4]. Here we investigate the role of MAO in neuronal cell death, which has particular relevance to the loss of dopaminergic neurons in Parkinson’s disease. Apoptosis was induced in human neuroblastoma (SH-SY5Y) cells using the protein kinase inhibitor, staurosporine (STS)[5]. In this model, the mitochondrial (caspase-9) pathway was activated 1 hour post treatment, but not the receptor mediated (caspase-8) pathway. This was followed by activation of the downstream apoptotic executioner caspase-3. Activation of caspase cascades was preceded by a dramatic and increased production of ROS evident within 1 hour of treatment. MAO activity was significantly increased during STS-induced apoptosis, peaking after 1 hour treatment, accompanied by an increase in MAO protein, but not MAO mRNA. All these events were associated with activation of the mitogen activated protein kinase (MAPK) enzymes JNK and p38, and depleted levels of the anti-apoptotic protein Bcl- 2. The specific MAO inhibitor, clorgyline, significantly protected cells from STS-induced-apoptosis, and reduced the effects on MAPK signalling and survival proteins. This suggests an involvement of MAO in the apoptotic cascade and signifies the involvement of MAPK signalling in MAO-mediated cell death. The antioxidant N-acetyl cysteine (NAC) also protected cells from apoptosis, to a similar extent to clorgyline, but the antioxidant vitamin C was less effective. In turn clorgyline and NAC dramatically reduced ROS production following STS treatment whilst vitamin C again was less effective. The use of anti-oxidants targeted to mitochondria will allow us to confirm whether most of the ROS produced is derived from mitochondria. In conclusion, our data provide evidence that MAO, through its production of ROS as a by-product of its catalytic activity, is recruited by the cell to enhance apoptotic signaling.