Due to being sessile, plants develop a broad range of defense pathways when they face abiotic or biotic stress factors. Although plants are subjected to more than one type of stress at a time in nature, the combined effects of either multiple stresses of one kind (abiotic or biotic) or more kinds (abiotic and biotic) have now been realized in agricultural lands due to increases in global warming and environmental pollution, along with population increases. Soil-borne pathogens, or pathogens infecting aerial parts, can have devastating effects on plants when combined with other stressors. Obtaining yields or crops from sensitive or moderately resistant plants could be impossible, and it could be very difficult from resistant plants. The mechanisms of combined stress in many plants have previously been studied and elucidated. Recent studies proposed new defense pathways and mechanisms through signaling cascades. In light of these mechanisms, it is now time to develop appropriate strategies for crop protection under multiple stress conditions. This may involve using disease-resistant or stress-tolerant plant varieties, implementing proper irrigation and drainage practices, and improving soil quality. However, generation of both stress-tolerant and disease-resistant crop plants is of crucial importance. The establishment of a database and understanding of the defense mechanisms under combined stress conditions would be meaningful for the development of resistant and tolerant plants. It is clear that leaf pathogens show great tolerance to salinity stress and result in pathogenicity in crop plants. We noticed that regulation of the stomata through biochemical applications and some effort with the upregulation of the minor gene expressions indirectly involved with the defense mechanisms could be a great way to increase the defense metabolites without interfering with quality parameters. In this review, we selected wheat as a model plant and Zymoseptoria tritici as a model leaf pathogen to evaluate the defense mechanisms under saline conditions through physiological, biochemical, and molecular pathways and suggested various ways to generate tolerant and resistant cereal plants.