Iron is an essential micronutrient for microorganisms, plants, animals, and humans. However, iron overload can damage the organism through a variety of mechanisms, including the induction of cell death. Ferroptosis is defined as an iron-dependent form of regulated cell death caused by unrestricted lipid peroxidation and subsequent membrane damage. Ferroptosis can be triggered through either the extrinsic or the intrinsic pathway. The extrinsic pathway is initiated through the regulation of transporters (e.g., inhibition of the amino acid antiporter system xc- or activation of the iron transporters transferrin and lactotransferrin), whereas the intrinsic pathway is mainly induced by blocking the expression or activity of intracellular antioxidant enzymes, such as glutathione peroxidase 4 (GPX4). In addition to small-molecule compounds and drugs, certain stresses (e.g., high temperature, low temperature, hypoxia, and radiation) induce ferroptotic cell death. The abnormal regulation of this process, which is connected to protein degradation pathways, such as autophagy and the ubiquitin-proteasome system, is associated with various pathological conditions, including acute tissue damage, infection, cancer, and neurodegeneration. Here, we discuss the core process and regulation of ferroptosis in mammalian cells, as well as its therapeutic implications in disease.