Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are generated by mitochondrial and enzymatic sources in all cells. If left unchecked, these ROS can cause oxidative damage to DNA, proteins, and membrane lipids. Glutathione peroxidase-1 (GPx-1) is an intracellular antioxidant enzyme that reduces hydrogen peroxide to water, limiting its harmful effects. Certain ROS, like hydrogen peroxide, are essential for growth factor-mediated signal transduction, mitochondrial function, and maintaining normal thiol redox balance. Thus, GPx-1 also modulates these processes by limiting hydrogen peroxide accumulation. This review explores the molecular mechanisms involved in regulating GPx-1 expression and function, emphasizing its role in modulating cellular oxidant stress and redox-mediated responses. As a selenocysteine-containing enzyme, GPx-1 expression is subject to unique forms of regulation involving selenium and selenocysteine incorporation during translation. GPx-1 has been implicated in the development and prevention of various diseases, including cancer and cardiovascular disease. The review discusses the role of GPx-1 in these diseases and speculates on potential future therapies to harness its beneficial effects.Reactive oxygen species (ROS) such as superoxide and hydrogen peroxide are generated by mitochondrial and enzymatic sources in all cells. If left unchecked, these ROS can cause oxidative damage to DNA, proteins, and membrane lipids. Glutathione peroxidase-1 (GPx-1) is an intracellular antioxidant enzyme that reduces hydrogen peroxide to water, limiting its harmful effects. Certain ROS, like hydrogen peroxide, are essential for growth factor-mediated signal transduction, mitochondrial function, and maintaining normal thiol redox balance. Thus, GPx-1 also modulates these processes by limiting hydrogen peroxide accumulation. This review explores the molecular mechanisms involved in regulating GPx-1 expression and function, emphasizing its role in modulating cellular oxidant stress and redox-mediated responses. As a selenocysteine-containing enzyme, GPx-1 expression is subject to unique forms of regulation involving selenium and selenocysteine incorporation during translation. GPx-1 has been implicated in the development and prevention of various diseases, including cancer and cardiovascular disease. The review discusses the role of GPx-1 in these diseases and speculates on potential future therapies to harness its beneficial effects.