Drought stress is considered one of the major constraints to crop production with devastating effects worldwide. Methylglyoxal (MG) homeostasis plays an essential role in promoting plant growth, development, metabolic adaptation, signal transduction, and thereby responses to drought stress. Manipulation of genes encoding aldosealdehyde reductases (ALRs), aldo-keto reductases (AKRs), genes that are involved in maintaining high ascorbate:glutathione (AsA:GSH), glutathione:glutathione disulfide (GSH:GSSG) contents and ratios, as well as jasmonic acid (JA) biosynthesis are of critical importance for improving MG detoxification, and thereby tolerance to drought stress. MG detoxification by maintaining optimal abscisic acid (ABA), JA, salicyclic acid (SA), and brassinosteroid (BR) homeostasis and crosstalk is also essential to optimize plant performance under both normal and drought stress conditions.