The last two decades have brought forth compelling new findings showing that aberrant cell cycle reentry results in death of mature neurons [1-3]. The cell cycle is an irreversible, ordered set of events [4], that normally leads to cellular division [5-7]. The release of cells from a quiescent state (G0) results in their entry into the first gap phase (G1), during which the cells prepare for DNA replication in the synthetic phase (S). This is followed by the second gap phase (G2) and mitosis phase (M). After the cell has split into its two daughter cells, the cell enters either G1 or G0. Mature neurons normally maintain themselves in G0 resting phase. Although they are unable to divide once differentiated, mature neurons do reenter cell cycle in certain pathological conditions. However, these mature neurons that reenter cell cycle neither revert to the earlier G0 nor advance to a new G0 phase. This presents a critical dilemma from which death may be an unavoidable, but necessary, outcome for these critical cells.