Alternative splicing plays a prevalent role in generating functionally diversified proteomes from genomes with a more limited repertoire of protein-coding genes. Alternative splicing is frequently regulated with cell type or developmental specificity and in response to signaling pathways, and its mis-regulation can lead to disease. Co-regulated programs of alternative splicing involve interplay between a host of cis-acting transcript features and trans-acting RNA-binding proteins. Here, we review the current state of understanding of the logic and mechanism of regulated alternative splicing and indicate how this understanding can be exploited to manipulate splicing for therapeutic purposes.