AMPA receptors mediate fast synaptic transmission at excitatory synapses in the CNS and are crucial during neuronal development, synaptic plasticity and structural remodeling. AMPA receptors lacking GluR2 subunits are permeable to Ca²⁺ and Zn²⁺. Ca²⁺ permeation through AMPA receptors is crucial in several forms of synaptic plasticity and cell death associated with neurological diseases and disorders. The subunit composition and Ca²⁺ permeability of AMPA receptors are not static, but they are dynamically remodeled in a cell- and synapse-specific manner during development and in response to neuronal activity, sensory experience and neuronal insults. Exciting new research shows that these changes arise not only because of regulated expression of the AMPA receptor subunit GluR2, but also as a consequence of RNA editing, receptor trafficking and dendritic protein synthesis. This article reviews new insights into the role of Ca²⁺-permeable AMPA receptors in neuronal function and survival.