The non-coding genome and regulatory RNAs hold substantial promise for precision medicine, particularly in cancer, where dysregulation of these elements contributes to tumour progression, metastasis, and therapy resistance. Despite technological advancements, the comprehensive understanding of non-coding RNAs and their role in cancer remains fragmented and incomplete. Here we present recent discoveries from our laboratory aimed at overcoming these limitations. On one hand, we investigated the transcriptional and epigenetic programs underlying cancer evolution using single-cell omics and genomic barcoding. In Triple-Negative Breast Cancer models, we found that cancer evolution can be driven by pre-encoded factors. We identified transcriptional states and DNA accessibility profiles linked to tumour initiation and drug tolerance, highlighting the complexity of cancer. In parallel, we are exploiting new third-generation technologies, such as Oxford Nanopore Technology (ONT), which can sequence long, possibly full-length RNA transcripts, enabling the accurate detection of isoforms, alleles, and transcripts that are traditionally difficult to resolve with short reads. Notably, RNA modification pathways are often dysregulated in human cancer and may represent new targets for cancer therapy. Direct RNA sequencing (dRNA-seq) can also capture nucleotide modifications as they alter the signal recorded by the ONT sequencing platform, opening new avenues for epitranscriptomics research.