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Diabetes mellitus is a global metabolic disorder characterized by progressive pancreatic β-cell failure, which leads to inadequate insulin secretion, often in combination with insulin resistance, and ultimately disrupts glucose homeostasis. The Integrated Stress Response (ISR), a crucial signaling network that enables cells to maintain homeostasis under endogenous and exogenous pressures, has garnered increasing attention for its role in regulating islet β-cell function and contributing to their failure. In recent years, a growing body of evidence has revealed that the ISR acts as a dual-edged sword in the onset and progression of diabetes. On the one hand, ISR activation can transiently relieve biosynthetic stress and help preserve cellular homeostasis. On the other hand, persistent or dysregulated ISR signaling is increasingly associated with impaired insulin production, loss of β-cell identity, and cell death in diabetes. In this Review, we summarize the molecular architecture of the ISR, focus on its regulatory role in pancreatic β-cell stress biology, and examine how ISR-related pathways are engaged in monogenic diabetes, type 1 diabetes, and type 2 diabetes. We further evaluate current therapeutic strategies targeting ISR-associated pathways and highlight the central translational challenge in this field, aiming to provide a theoretical basis and novel insights for a deeper understanding of the molecular mechanisms driving diabetic β-cell failure and for the development of novel precision therapeutic approaches.