It has been over 20 years since JUN amino-terminal kinases (JNKs) were identified as protein kinases that are strongly activated by cellular stress and that have a key role in apoptosis. Examination of Jnk-knockout mice and characterization of JNK behaviour in neuronal cells has further revealed the importance of the JNK family in the nervous system. As well as regulating neuronal death, JNKs govern brain morphogenesis and axodendritic architecture during development, and regulate important neuron-specific functions such as synaptic plasticity and memory formation. This Review examines the evidence that the spatial segregation of JNKs in neurons underlies their distinct functions and that compartment-specific targeting of JNKs may offer promising new therapeutic avenues for the treatment of diseases of the nervous system, such as stroke and neurodegenerative disorders.