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Temperatures above the optimal temperature range for plant growth and reproduction cause deleterious cellular damage, which in turn affects plant productivity. To relieve these effects, plants adapt to high temperature by activating a series of physiological and biochemical changes necessary to reestablish a new cellular homeostasis compatible with the increase in temperature. The genetic control of the heat shock (HS) response is quite complex and requires the activation of a network of genes, involved in the perception and transduction of the HS signal, which, in turn, trigger the up-regulation of other target genes. The induced genes code for proteins and enzymes (HS proteins, active oxygen detoxifying enzymes), playing a direct role in the protection of cellular and subcellular organelles or genes encoding enzymes involved in the biosynthesis of protective compatible compounds (sugars, polyols, betaines). Membrane lipid instauration, controlled by desaturase genes, is also a critical component of thermotolerance. This chapter covers the principal aspects of the plant HS response and the role of different class of genes in the acquisition of thermotolerance. The molecular breeding strategies currently available to alter genetically the level of the protective proteins, enzymes and molecules, that may ameliorate plant tolerance and productivity under high temperature stress, will be also discussed.