RNA-derived stress-induced RNAs (tiRNAs) are fragments generated from transfer RNA (tRNA) molecules and are gaining recognition for their pivotal role in cancer progression. These tiRNAs emerge under conditions of cellular stress through the targeted cleavage of mature tRNA by the enzyme angiogenin. As key mediators in the cellular stress response, tiRNAs influence several critical processes. Under stress conditions, angiogenin is activated and cleaves tRNAs at specific sites, leading to the formation of tiRNAs. This cleavage is not random but occurs at precise anticodon loops, producing fragments that are uniquely suited to participate in stress responses. These tiRNAs then engage in a variety of cellular mechanisms primarily aimed at survival and adaptation. They help reprogram protein synthesis by modulating translation, a process critical for reshaping cellular functions under stress. This modulation often involves selective translation of mRNAs that encode proteins crucial for stress mitigation. Moreover, tiRNAs play a significant role in inhibiting apoptosis, the programmed cell death pathway, which is often activated under severe stress conditions. By blocking apoptosis, tiRNAs allow cells additional time to repair and survive. They are also involved in the degradation of mRNAs, selectively removing messages that encode unnecessary or detrimental proteins during stress conditions. Additionally, tiRNAs contribute to the formation of stress granules, which are aggregates of proteins and RNAs that appear in the cytoplasm during stress and help in managing protein synthesis and stabilizing cellular metabolism. This chapter on tiRNAs delves into their genesis, detailing the molecular mechanisms of their formation, their functional roles in cellular stress response, and their significant impact on disease management, particularly in the context of cancer. Understanding the role of tiRNAs in these processes not only illuminates a novel aspect of RNA biology but also opens potential therapeutic avenues where tiRNAs could be targeted to enhance cancer treatment or modulate stress responses more broadly. This growing body of research highlights the complex and nuanced roles that small RNAs play in cellular homeostasis and disease, offering new insights into the intricate dance of molecular interactions within cells.