The evolution of alternative splicing in eukaryotes greatly expanded the number of functionally distinct proteins that could be produced from a finite gene pool. Extensive in the brains of higher organisms, alternative splicing might be the primary mechanism for generating the spectrum of protein activities that support complex brain functions. Alternative splicing is controlled at the level of individual neurons to custom design proteins for optimal performance. The expression profiles of splice isoforms are modified during development and as neuronal activity changes. Alternative splicing can lead to incremental, long lasting changes in ion channel and receptor activities, independent of changes in gene transcription. Recent studies of tissue-specific splicing factors are revealing how coordinated alterations in alternative splicing of RNA transcripts control synaptic function.