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Summary Alternative splicing is a post-transcriptional regulatory mechanism producing distinct mRNA molecules from a single pre-mRNA with a prominent role in the development and function of the central nervous system. We used long-read isoform sequencing to generate full-length transcript sequences in the human and mouse cortex. We identify novel transcripts not present in existing genome annotations, including transcripts mapping to putative novel (unannotated) genes and fusion transcripts incorporating exons from multiple genes. Global patterns of transcript diversity are similar between human and mouse cortex, although certain genes are characterized by striking differences between species. We also identify developmental changes in alternative splicing, with differential transcript usage between human fetal and adult cortex. Our data confirm the importance of alternative splicing in the cortex, dramatically increasing transcriptional diversity and representing an important mechanism underpinning gene regulation in the brain. We provide transcript-level data for human and mouse cortex as a resource to the scientific community., Graphical abstract, Highlights • There is widespread transcript diversity in the cortex and many novel transcripts • Some genes display big differences in isoform number between human and mouse cortex • There is evidence of differential transcript usage between human fetal and adult cortex • There are many novel isoforms of genes associated with human brain disease, Leung et al. use long-read sequencing to annotate RNA isoforms in the human and mouse cortex. They identify novel transcripts and evidence for differential transcript usage between the fetal and adult cortex. Their data confirm the importance of alternative splicing as a mechanism underpinning gene regulation in the brain.