Cellular immortalization is a crucial and early step during the development of cancer, while normal primary mammalian cells reach replicative limitation after several passages in vitro, called replicative senescence. Senescent cells have altered cell morphology and gene expression patterns with preserved metabolic activity, which are quite distinct from others. Interestingly, senescent cells have also been detected in vivo, particularly in benign lesions of human tumors. Senescence would constitute a protective barrier against cancerous immortalization. In other words, during tumorigenesis, cancer cells acquire genetic alterations to override senescence. By using high throughput genetic screening to search for genes involved in senescence, several candidates for oncogenes and putative tumor suppressor genes have been recently isolated, including subtypes of micro- RNAs. These findings offer new perspectives in the senescence biology and open new avenues for cancer therapy.