Induced Systemic Resistance (ISR) is an important biological defense mechanism in plants, which enhances their resistance to a wide range of pathogens and abiotic stresses. ISR is triggered by beneficial microorganisms, particularly Plant Growth Promoting Rhizobacteria (PGPR) and involves complex molecular interactions among key signaling pathways, including salicylic acid (SA), jasmonic acid (JA), ethylene (ET), abscisic acid (ABA) and Reactive Oxygen Species (ROS). This review explores the mechanistic basis of ISR, focusing on the molecular crosstalk and epigenetic memory that primes plants for enhanced stress tolerance. The integration of ISR with climate resilience strategies is highlighted, addressing the potential of ISR to mitigate the impacts of climate variability, including heatwaves, floods and elevated CO₂ levels. Additionally, practical challenges such as field-level validation, cost-effectiveness and formulation development are discussed, alongside the technological innovations that may enhance ISR applications in sustainable agriculture. This work aims to provide a comprehensive understanding of ISR's molecular foundations and its potential for climate-resilient agriculture, with a focus on scalable and economically viable solutions. Future directions, including the integration of ISR with precision agriculture and the use of biotechnological advancements such as CRISPR-Cas systems, offer promising avenues for enhancing ISR efficiency and expanding its applicability across diverse agricultural systems. This review aims to contribute to the development of ISR-based strategies that can promote long-term agricultural sustainability and global food security.