Reductive stress is defined as a condition characterized by excess accumulation of reducing equivalents (e.g., NADH, NADPH, GSH), surpassing the activity of endogenous oxidoreductases. Excessive reducing equivalents can perturb cell signaling pathways, change the formation of disulfide bonding in proteins, disturb mitochondrial homeostasis or decrease metabolism. Reductive stress is influenced by cellular antioxidant load, its flux and a subverted homeostasis that paradoxically can result in excess ROS induction. Balanced reducing equivalents and antioxidant enzymes that contribute to reductive stress can be regulated by Nrf2, typically considered as an oxidative stress induced transcription factor. Cancer cells may coordinate distinct pools of redox couples under reductive stress and these may link to biological consequences from both molecular and translational standpoints. In cancer, there is recent interest in understanding how selective induction of reductive stress may influence therapeutic management and disease progression.