Glaucoma results from degeneration of the retinal ganglion cells (RGCs) that connect retina to brain, and is both the leading cause of irreversible blindness and currently untreatable. Any treatment would require replacement of lost RGCs, and while cell therapy offers one route for this, reprogramming of endogenous cells provides an alternative. The transcription factor Klf4 is a potent reprogramming factor but its role in RGC competence and specification have remained incompletely understood. Now, Maurício Rocha-Martins, Mariana Silveira and colleagues address this issue with a comparative loss- and gain-of-function analysis. Deletion of Klf4 in mouse retinal progenitor cells or in a whole zebrafish mutant line does not perturb RGC generation. In contrast, Klf4 overexpression changes the cell types that late retinal progenitor cells give rise to, leading to an increase in RGC marker expression and inducing cells to prematurely exit the cell cycle. Induced RGCs (iRGCs) express genes defined as RGC specific and downregulate photoreceptor differentiation genes; surprisingly, they do not express Brn3a or Brn3b, genes previously implicated in RGC maturation and survival, nor do they require their expression for long term survival and axonogenesis. Klf4 is thus sufficient to induce RGC generation in vivo, and is a promising candidate for reprogramming approaches to glaucoma.