Drought is a key factor affecting coffee plant development and production. In the context of global warming, the generation of drought-tolerant coffee varieties has now turned into one of the priorities of many coffee research institutes. At the genetic level, it is well known that variability exists within the Coffea genus regarding the tolerance to drought-tolerant. During the last decade, several drought-tolerant clones of C. canephora Conilon have been characterized as vigorous plants with high productivity throughout years under drought stress. Physiological analyses suggested that drought tolerance could be a direct consequence of better root development or of enhanced activity of antioxidant enzymes. The recent advances in coffee genomics mainly expressed sequence tag (EST) sequencing projects now open the way to study the molecular and genetic determinism of drought tolerance and to the identification of molecular markers that could be used to speed up coffee breeding programs. With the aim to investigate the molecular mechanisms underlying drought tolerance in coffee plants of C. canephora and C. arabica, qPCR experiments identified more than 80 candidate genes (CGs) presenting differential gene expression between drought-tolerant and drought-susceptible clones/cultivars cultivated under different (with or without) irrigation conditions. Based on the results obtained in C. canephora, we concluded that factors involved a complex network of responses probably involving the abscisic (ABA) signaling pathway and nitric oxide (NO) are major molecular determinants that might explain the better efficiency in controlling stomata closure and transpiration displayed in drought-tolerant clones. In the drought-tolerant I59 cultivar C. arabica, many CGs involved in the signal transduction pathway of drought stress but also in the synthesis of several biochemical compounds (derivative-sugars etc...), were highly over-expressed under drought compared to drought-susceptible