All cancers arise from alterations in the DNA sequence of cancer cell genomes. The advent of Next-Generation Sequencing (NGS) has enabled researchers to examine the cancer genome at an unprecedented scale. NGS approaches—such as whole-genome, whole-exome, and transcriptome sequencing—have greatly expanded our understanding of oncogenic genomic changes, including point mutations, insertions and deletions, copy-number variations, and structural variants. Moreover, NGS has facilitated the discovery of novel oncogenes and helped elucidate the molecular mechanisms underlying tumor initiation, metastasis, and the complexity and heterogeneity of cancer. These insights support the development of more effective therapeutic strategies, inform treatment selection, and guide diagnostic and preventive approaches.