<p>The biggest challenge for the agricultural community is feeding the growing global population. This challenge is not new; the world has witnessed population growth and an accompanying increase in food production over the past several decades. However, it now seems to be becoming more difficult as the climate is changing and becoming increasingly unpredictable. The current scenario of unpredictable climate changes imposes a significant risk to crop production worldwide. Efforts must be intensified to provide sustainable solutions to this issue. Sustainable development in agriculture largely depends on the development of stress-tolerant cultivars. In this regard, understanding biotic and abiotic stress tolerance mechanisms in plants is crucial. Recent advancements in various omics tools have helped enhance our understanding of the physiological processes involved in stress tolerance. Compared to other omics tools, genomics and transcriptomics are being widely explored, particularly to understand the genetic regulations and molecular pathways involved in stress tolerance mechanisms. Omics tools generate vast amounts of data, and it often becomes challenging to draw meaningful conclusions. However, the efficient integration of omics will help in better understanding the complex molecular mechanisms involved in stress tolerance. This special issue focuses on innovative strategies involving omics tools and integrated omics approaches for enhancing plant resilience under stress. The special issue features articles defining the role of circular RNAs, double-stranded RNA (dsRNA), and overall transcriptional activity under stress conditions. Additionally, it showcases the application of single-cell multi-omics and integrative omics in plant science. Similarly, a commentary on the exploration of big data-based approaches for sustainable agriculture is also included. This special issue will be helpful in understanding the potential of integrated omics approaches for biotic and abiotic stress tolerance in plants.</p>