Key message <p>The cytokinin regulatory system (CRS) is important for plant adaptation to adverse environmental conditions, including drought and heat stress. CRS represents a promising biotechnological target to improve crop tolerance to these stresses.</p> Abstract <p>Drought and heat are widespread natural phenomena leading to stress in plants and a significant yield reduction in crop plants. Tolerance of drought and heat determines the productivity of major crops. The global climate forecast predicts further temperature increase and worsening water shortage in the very near future. Plants can withstand heat stress and water scarcity using their adaptive hormonal system. Among the plant hormones, cytokinins (CKs), which are best known for their numerous functions in regulating growth and development, play a significant role in plants’ responses to heat and water stress. This review summarizes the effects of CK on drought and heat tolerance in common agricultural plants, and strategies to protect these plants are described. Particular attention is paid to biotechnological approaches targeting the cytokinin regulatory system (CRS) to preserve crop phenotype and yield under stress conditions. Interestingly, CKs have been reported to improve drought/heat resistance both by increased and decreased signaling. We propose a rational explanation for this apparent paradox of CK action. This review aims to be helpful to plant biotechnologists and genetic engineers in selecting suitable CRS targets that could serve as tools to generate new drought- and heat-tolerant crop varieties.</p>