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Drought stress is generally considered as a negative factor in agriculture, being responsible for severe yield losses. However, medicinal plants grown under semi-arid conditions usually produce higher concentrations of active substances than same species grown under moderate climates. Currently, only limited information is available on the physiological background of this well-known phenomenon. To elucidate this issue, we review here the existing findings to unveil the underlying metabolic mechanisms. Indeed, we found that the drought stress-related metabolic changes are responsible for the accumulation of active substances in semi-arid regions. In particular, the biochemical coherences are as follows: due to limited water supply and much higher light intensities, the plants suffer from drought stress. Then, due to water shortage, stomata are closed and the uptake of CO2 decreases markedly. As a result, CO2 fixation via Calvin cycle decreases. This decline of CO2 fixation leads to a massive decrease in the consumption of reduction equivalents (NADPH + H+), generating in turn a massive oversupply of NADPH + H+. As a consequence, metabolic processes are pushed towards the synthesis of highly reduced compounds, such as isoprenoids, phenols, or alkaloids. Our findings open the path to design practical approaches for enhancing the product quality of spice and medicinal plants. Indeed, by deliberately applying moderate drought stress during their cultivation, the quality of spice and medicinal plants can be enhanced significantly.