Drought stress restricts plant growth and development by altering metabolic activity and biological functions. However, plants have evolved several cellular and molecular mechanisms to overcome drought stress. Drought tolerance is a multiplex trait involving the activation of signaling mechanisms and differentially expressed molecular responses. Broadly, drought tolerance comprises two steps: stress sensing/signaling and activation of various parallel stress responses (including physiological, molecular, and biochemical mechanisms) in plants. At the cellular level, drought induces oxidative stress by overproduction of reactive oxygen species (ROS), ultimately causing the cell membrane to rupture and stimulating various stress signaling pathways (ROS, mitogen-activated-protein-kinase, Ca2+, and hormone-mediated signaling). Drought-induced transcription factors activation and abscisic acid concentration co-ordinate the stress signaling and responses in cotton. The key responses against drought stress, are root development, stomatal closure, photosynthesis, hormone production, and ROS scavenging. The genetic basis, quantitative trait loci and genes of cotton drought tolerance are presented as examples of genetic resources in plants. Sustainable genetic improvements could be achieved through functional genomic approaches and genome modification techniques such as the CRISPR/Cas9 system aid the characterization of genes, sorted out from stress-related candidate single nucleotide polymorphisms, quantitative trait loci, and genes. Exploration of the genetic basis for superior candidate genes linked to stress physiology can be facilitated by integrated functional genomic approaches. We propose a third-generation sequencing approach coupled with genome-wide studies and functional genomic tools, including a comparative sequenced data (transcriptomics, proteomics, and epigenomic) analysis, which offer a platform to identify and characterize novel genes. This will provide information for better understanding the complex stress cellular biology of plants.