Plants are sessile organisms. They have to endure the environmental catastrophe throughout their life cycle. To survive in these hostile surroundings, plants posses an efficient and fine-tuned defense mechanism. This is a well established fact that various defense molecules viz. salicylic acid (SA), jasmonic acid, abscisic acid (ABA), ethylene (ET) and so on, are working in a synergistic as well as antagonistic fashion to establish and activate the effective defense mechanism. Interestingly, glutathione is gaining a gradual importance in this complex scenario. This multifunctional biomolecule exists in two forms. The reduced form, viz. GSH, is primarily present at millimolar concentrations in various plant tissues as compared to its oxidized form, glutathione disulfide, GSSG. Proteo-genomics analysis confirmed that GSH plays a vital role in plant resistance against biotic and abiotic stresses by stimulating various defense genes and proteins. In recent times, it has been reported that modulation of GSH contents transmits information through diverse signaling mechanisms. GSH also modulates various stresses and defense related genes by interacting with ABA and ET in response to abiotic stress conditions. However, there are still many unanswered questions about the intricate molecular mechanism of GSH’s contribution in plant defense. With these backgrounds, presently we primarily discussed the transcriptomic changes under stress conditions in Arabidopsis thaliana at altered GSH contents. Transcriptomic profiling of phytoalexin-deficient mutant (pad2.1), a GSH depleted A. thaliana mutant, in response to combined cold and osmotic stress treatment, was compared to that of A. thaliana ecotype Col-0, the wild type, with a view to identify the genes altered under changed GSH conditions to combat stress. It was evident from these datasets that the transcript level responses of pad2.1 to this treatment were massive. Again, analysis of combined cold and osmotic stress treated other mutants of Arabidopsis transcriptome was performed to elucidate the crosstalk between the ABA, ET and GSH. Results revealed the differential regulation of about 2313 and 4131 transcripts in A. thaliana mutants viz. ethylene insensitive (ein2) and ABA deficient 1(aba1.6) respectively. Together, present findings elucidate an active interplay of GSH with SA, ET, and ABA to combat environmental stress conditions in planta.