High-throughput RNA sequencing has revealed enormous diversity in mRNA transcripts however our understanding of the functional ramifications remains incomplete. A major driver of this diversity is alternative splicing and mounting evidence indicates that disrupted splicing contributes to cancer development and therapeutic resistance. We recently showed that widespread changes in alternative splicing accompany melanoma drug tolerance and resistance to MAPK therapies, and that targeting the splicing machinery can enhance responses to MAPK inhibition. To further define the contribution of transcript diversity to melanoma progression and therapy response, we applied Nanopore long-read sequencing to preclinical melanoma models and patient samples. This approach revealed an unexpectedly complex melanoma transcriptome, including ~12,000 previously unannotated transcripts and ~3,000 novel genomic loci, using stringent criteria. Many of these transcripts are detected in up to 80% of melanomas yet are largely absent from normal tissues and remain functionally uncharacterised. Integration of these data with proteomics revealed that some also encode novel protein isoforms. We are currently investigating how these melanoma-specific transcripts are regulated, their function, and the potential implications for developing new preventative and therapeutic strategies to improve outcomes for melanoma patients.