Simple SummaryBoth oxidative and reductive stress can be destructive to cells. Unlike oxidative stress, reductive stress and the therapeutic opportunities underlying the mechanisms of reductive stress in cancer, as well as how cancer cells reply to reductive stress, have attracted little interest and are not properly characterized. Selenium compounds have been demonstrated to have chemotherapeutic effects against cancer, and their anticancer mechanism is thought to be related to the formation of their metabolites. One of them is hydrogen selenide (H2Se), a highly reactive molecule with reducing properties. Unfortunately, most chemotherapeutic selenium compounds were studied under aerobic conditions, although solid tumors exhibit hypoxic conditions. Here, we show the latest reports on the mechanism of cellular recognition and reaction to reductive and oxidative stress as well as the mechanisms through which different types of selenium compounds can release H2Se and thereby can selectively affect reductive stress under controlled conditions, which may be crucial for their anticancer activity.AbstractRedox balance is important for the homeostasis of normal cells, but also for the proliferation, progression, and survival of cancer cells. Both oxidative and reductive stress can be harmful to cells. In contrast to oxidative stress, reductive stress and the therapeutic opportunities underlying the mechanisms of reductive stress in cancer, as well as how cancer cells respond to reductive stress, have received little attention and are not as well characterized. Therefore, there is recent interest in understanding how selective induction of reductive stress may influence therapeutic treatment and disease progression in cancer. There is also the question of how cancer cells respond to reductive stress. Selenium compounds have been shown to have chemotherapeutic effects against cancer, and their anticancer mechanism is thought to be related to the formation of their metabolites, including hydrogen selenide (H2Se), which is a highly reactive and reducing molecule. Here, we highlight recent reports on the molecular mechanism of how cells recognize and respond to oxidative and reductive stress (1) and the mechanisms through which different types of selenium compounds can generate H2Se (2) and thus selectively affect reductive stress under controlled conditions, which may be important for their anticancer effects.