During embryonic development, uncommitted pluripotent cells undergo progressive epigenetic changes that lock them into a final differentiated state. Can mammalian cells change identity within the living organism? Direct lineage reprogramming of cells has attracted attention as a means to achieve organ regeneration. However, it is unclear whether cells in the CNS are endowed with the plasticity to reprogram. Neurons in particular are considered among the most immutable cell types, able to retain their class-specific traits for the lifespan of the organism. Here we focus on two experimental paradigms, glia-to-neuron and neuron-to-neuron conversion, to consider how lineage reprogramming has challenged the notion of CNS immutability, paving the way for the application of reprogramming strategies to reshape neurons and circuits in vivo. Copyright © 2014 Elsevier Ltd. All rights reserved.