Reactive oxygen species (ROS) are oxygen-containing molecules that possess unpaired electrons. ROS are a normal component of cellular life, and accumulating evidence suggests that these molecules play critical roles in many important signal transduction pathways. However, maintaining a balance between ROS production and elimination is a crucial component of cellular homeostasis. Unregulated increases in cellular ROS can inflict significant physical damage on subcellular structures, such as mitochondria and lipid membranes. Furthermore, accumulating evidence asserts that ROS can play an aberrant role in cellular signaling if their production is left unchecked. This review is a discussion of the interaction between ROS and the Janus Kinase 2 (Jak2) signal transduction pathway in the context of three highly prevalent diseases; diabetes, atherosclerosis and cardiac ischemia-reperfusion injury. ROS-mediated Jak2 activation contributes to the progression of diabetic nephropathy, atherosclerosis and acute cardiac ischemia-reperfusion injury. Interestingly, this mechanism also appears to play a cardioprotective role in preconditioned cardiac ischemia-reperfusion injury. Currently, its role in diabetic cardiomyopathy is unclear. Thus, the Jak2/ROS relationship appears to have significant consequences for human health, as indicated by its prominent role in several highly prevalent disorders.