Once thought of exclusively as damaging molecules, reactive oxygen species (ROS) are becoming increasingly appreciated for the role they play in cellular signaling through redox biology. Notably, mitochondria are a major source of ROS within a cell (mROS). Mounting evidence now clearly shows that mROS are critical for intracellular redox signaling by which they contribute to a plethora of cellular processes such as proliferation. mROS are essential for physiological cell proliferation, particularly by the regulation of hypoxia inducible factors (HIFs) under hypoxia. mROS are also vital mediators of growth factor signaling cascades such as angiotensin II (Ang II) and T-cell receptor (TCR) signaling. Pathological proliferative diseases such as cancer utilize mROS to their advantage, aberrantly activating growth factor signaling cascades and perpetuating angiogenesis under hypoxia. This review discusses how mROS positively regulate mitogenic cellular signaling through redox biology, which is critical for both physiological and pathological proliferation.