Parkinson’s disease (PD) is caused by the loss of dopaminergic neurons in the substantia nigra, probably through apoptosis. Albéri and co-workers now report that the engrailed (En) genes are required to prevent apoptosis of newly-born mesencephalic dopaminergic neurons (see p. 3229). The homeobox transcription factors En1 and En2 are expressed in these neurons from early development to adulthood. In En1/En2-null mice, in which large areas of the brain are lost, mesencephalic dopaminergic neurons are generated and become postmitotic but are then lost by birth. The researchers show that this loss occurs by E14 through apoptosis. In vitro cell-mixing and RNAi experiments indicate that apoptosis induction occurs within 24 hours of En downregulation because of a cell-autonomous requirement for En. The researchers speculate that small changes in En expression could underlie the slow degeneration of dopaminergic neurons seen in PD.