<p>The present global climate change scenario has led to a drastic decline in agricultural production in various regions worldwide. Abiotic (drought, heat, salinity, and excessive rainfall) and biotic (pests and diseases) stress significantly reduce the yields of many cultivated crops. This unprecedented loss in crop productivity poses a severe threat to future food supply and leads to nutritional insecurity in several parts of the world. Pearl millet is a climate-resilient, nutrient-dense, multipurpose crop that serves as an alternative to achieve food security owing to its superior climate adaptation. Prominent research efforts have been made to enhance climate resilience in pearl millet using conventional breeding. Genomic advances, including marker-assisted selection, quantitative trait loci mapping, and genome-wide association studies, helped achieve these research targets. Key achievements of these approaches include the identification of Meta-QTL1.1 and Meta-QTL2.4 for stress resistance and disease resistance, respectively. The development of high-quality reference genome assemblies of 843B, ICMR 06777 (A1 cytoplasm maintainer and restorer lines) and an improved Tift, broadened the scope of biotechnological research in the crop. More recently, multi-omics approaches, including transcriptomics, proteomics, and metabolomics, have provided insights into the key genes and pathways involved in the stress responses of pearl millet. Integrating multi-omics with advanced biotechnology tools, such as gene editing, offers a holistic approach addressing trait-based breeding challenges in pearl millet. This review highlights the pivotal role of these tools in understanding the molecular pathways and key genes involved in stress response mechanisms of pearl millet, while also outlining future direction of research.</p>