Cellular senescence is a complex and tightly regulated process characterized by the permanent arrest of the cell cycle in response to various forms of stress. In this chapter, we will explore the primary mechanisms underlying the induction of senescence, highlighting the molecular pathways involved. Special attention will be given to the relationship between cellular senescence and the APOE (apolipoprotein E) gene, which plays an important role in lipid metabolism, neurobiology, and several age-related diseases. We will examine how the activation of DNA damage response pathways—often triggered by genotoxic stimuli such as ionizing radiation, chemical exposure, or oxidative stress—can induce premature senescence and simultaneously lead to dysregulation of APOE expression or function. Additionally, we will discuss DNA repair mechanisms and how their failure contributes to the initiation of senescence-associated signaling pathways. By integrating these topics, this chapter aims to provide a comprehensive overview of the interplay between genotoxic stress, cellular senescence, and APOE regulation, offering insights into their potential roles in aging and disease development.