Alternative usage of exons provides genomes with plasticity to produce different transcripts from the same gene, modulating the function, localization, and life cycle of gene products. It affects most human genes. For a limited number of cases, alternative functions and tissue-specific roles are known. However, recent high-throughput sequencing studies have suggested that much alternative isoform usage across tissues is nonconserved, raising the question of the extent of its functional importance. We address this question in a genome-wide manner by analyzing the transcriptomes of five tissues for six primate species, focusing on exons that are 1:1 orthologous in all six species. Our results support a model in which differential usage of exons has two major modes: First, most of the exons show only weak differences, which are dominated by interspecies variability and may reflect neutral drift and noisy splicing. These cases dominate the genome-wide view and explain why conservation appears to be so limited. Second, however, a sizeable minority of exons show strong differences between tissues, which are mostly conserved. We identified a core set of 3,800 exons from 1,643 genes that show conservation of strongly tissue-dependent usage patterns from human at least to macaque. This set is enriched for exons encoding protein-disordered regions and untranslated regions. Our findings support the theory that isoform regulation is an important target of evolution in primates, and our method provides a powerful tool for discovering potentially functional tissue-dependent isoforms.