Crops and other plants in natural conditions are routinely affected by several stresses acting simultaneously or in sequence. In areas affected by drought, plants may also be exposed to enhanced UV-B radiation (280-315nm). Each of these stress factors differently affects cellular metabolism. A common consequence of plant exposure to the separate action of water deficit and UV-B radiation is the enhanced generation of reactive oxygen species (ROS) causing damage to proteins, lipids, carbohydrates and DNA. Despite this destructive activity, ROS also act as signalling molecules in cellular processes responsible for defence responses. Plants have evolved many physiological and biochemical mechanisms that avoid or tolerate the effects of stress factors. Water deficit avoidance leads to stomatal closure, stimulation of root growth, and accumulation of free proline and other osmolytes. Secondary metabolites (flavonols, flavones and anthocyanins) that accumulate in epidermal cells effectively screen UV-B irradiation and reduce its penetration to mesophyll tissue. The coordinated increased activity of the enzymatic antioxidant defence system such as up-regulation of superoxide dismutase, catalase, guaiacol peroxidase, ascorbate peroxidase and glutathione reductase is an important mechanism of tolerance to water deficit and UV-B radiation. The accumulation of low molecular antioxidants (proline, glycine betaine, ascorbate and glutathione) can also contribute to tolerance to water deficit. Polyamines, tocopherol, carotenoids, alkaloids, flavonoids and other secondary metabolites participate in the removal of ROS under conditions of increased UV-B radiation. The combination of water deficit and UV-B radiation induces responses that can be antagonistic, additive or synergistic in comparison with the action of single stresses. UV-B radiation may enhance resistance to water deficit and vice versa. Hydrogen peroxide, nitric oxide (NO), abscisic acid (ABA), jasmonic acid, ethylene, and salicylic acid participate in the activation of defence mechanisms. The involvement of these molecules in cross-resistance may rely on activation of enzymatic and non-enzymatic antioxidant systems, enzymes of flavonoid biosynthesis and the accumulation of low-molecular-weight osmolytes as well as regulation of stomatal closure. However, under the conditions of prolonged action of stressors or in the case where one of them is severe, the capacity of the defence system becomes exhausted, leading to damage and even death.