Ferroptosis, an iron-dependent form of programmed cell death, defined in 2012. It is triggered by the excessive accumulation of lipid peroxides and disruption of oxidative homeostasis, and is characterized by mechanisms and morphological features distinct from those of apoptosis, necrosis, and autophagy. Glutathione peroxidase 4 (GPX4), the fourth member of the glutathione peroxidase (GPX) family, is the core regulator of ferroptosis. It maintains redox homeostasis and prevents ferroptosis by relying on glutathione (GSH) to catalyze the reduction of lipid hydroperoxides (LOOH) to their corresponding lipid alcohols (LOH). Dysfunction of GPX4 is linked to various diseases like cancer drug resistance and neurodegenerative disorders. Notably, post-translational modifications of GPX4 (e.g., ubiquitination/phosphorylation) are crucial in regulating ferroptosis, and the development of GPX4-targeted inhibitors has emerged as a novel strategy in cancer therapy. This review synthesizes the regulatory mechanisms and inhibitors of GPX4, and provides perspectives for future research.