It is well established that oxidative stress plays a central role in the onset and progression of over a 100 different diseases. Recently, a growing body of evidence has shown that chemicals/agents as diverse as aromatic compounds, UV radiation and redox-active metals also generate oxy-radicals in vivo and lead to cellular oxidative stress. In this study we have used mouse skin fibroblasts to study the effects of oxidative stress caused by organic aromatic compounds (xylene), UV radiation and redox-active metals. Specifically, we tested the effect of these treatments on intracellular GSH levels, as well as on protein S-thiolation. We show that acute exposure of these diverse set of conditions cause dramatic depletion of the intracellular GSH pool in mouse skin fibroblast cells. We also found evidence of synergistic effects of combined exposure to different sources of oxidative stress. Furthermore, we also found that these treatments also caused significant S-thiolation (protein mixed-disulfide formation) of a 70kDa cytosolic protein.