Cellular senescence and immortalization are critical processes in aging and cancer, necessitating advanced genomic techniques for in-depth understanding. This review explores methods such as gene expression profiling, whole genome sequencing, genome-wide association studies (GWAS), functional genomics screens, epigenomic profiling, and pathway analysis. These approaches reveal genetic and epigenetic changes in senescent and immortalized cells, unravel regulatory networks, and identify potential therapeutic targets. Key triggers such as mitochondrial dysfunction and oxidative stress are discussed, along with the role of the interferon pathway in senescence and important signaling pathways like IGF-1R/AKT and MAP kinase. Integrating these genomic insights enhances our knowledge of cellular senescence and immortalization, driving progress in aging and cancer research.