Several homeoproteins can function in a direct cell non-autonomous fashion to control various biological processes. In the developing nervous system, this mode of signaling has been well documented for Engrailed in the guidance of retinal ganglion cell axons and retino-tectal patterning. Engrailed is also a key factor for mesencephalic dopaminergic (mDA) neurons, not only during development but also in the adult. Haplodeficiency for Engrailed1 leads to progressive adult-onset loss of mDA neurons and several phenotypic alterations reminiscent of Parkinson’s disease (PD). Thanks to its transduction properties, Engrailed has been shown to confer neuroprotection in several experimental models of PD. Study of the mechanisms underlying these two Engrailed-mediated effects has revealed a key role of the translation regulation by Engrailed and uncovered an unsuspected link between a homeoprotein and mitochondrial activity. These studies highlight the crucial role of cellular energetic metabolism in neuron development, survival and neurodegeneration, and may help to identify novel therapeutic targets.