Necrosis is a sudden, traumatic, and non-programmed cell death occurring when cells are severely damaged beyond the threshold of a reasonable attempt to repair, or are subjected to noxious agents that are incompatible with survival, e.g., heat or mechanical trauma. Since all these events are highly intense and unexpected, necrosis is always seen as a premature and non-regulated death. Necrosis is therefore a passive and accidental event which occurs without the involvement of a pre-determined genetic program or biochemical steps. Morphologically, necrosis is characterized by lack of DNA fragmentation, rounding of the cell associated with gain in volume (oncosis), organelle swelling and, finally, membrane rupture. As a consequence, there is an uncontrolled release of all intracellular contents – included the Damage-Associated Molecular Patterns (DAMPs), such as the nuclear High Mobility Group Box-1 proteins (HMGB-1) and the mitochondrial DNA – able to damage the neighboring cells and to give rise to a strong inflammatory process. In fact, the inflammatory response that follows necrosis is a hallmark of this type cell death, while apoptosis accurately prevents the initiation of inflammation. For these reasons, necrosis may cause a wide and often irreversible organ damage and has been historically considered a clear sign of stress, injury, infection and tissue destruction, all linked to the pathogenesis of several diseases. Consistently, the presence of DAMPs in in the bloodstream is now considered an indicator of cellular necrosis.