Water scarcity is the most significant factor limiting coffee production, although some cultivars can still have important drought tolerance. This study analyzed leaf transcriptomes of two coffee cultivars with contrasting physiological responses, Coffea canephora cv. CL153 and Coffea. arabica cv. Icatu, subjected to moderate (MWD) or severe water deficits (SWD). We found that MWD had a low impact compared with SWD, where 10% of all genes in Icatu and 17% in CL153 reacted to drought, being mainly down-regulated upon stress. Drought triggered a genotype-specific response involving the up-regulation of reticuline oxidase genes in CL153 and heat shock proteins in Icatu. Responsiveness to drought also included desiccation protectant genes, but primarily, aspartic proteases, especially in CL153. A total of 83 Transcription Factors were found engaged in response to drought, mainly up-regulated, especially under SWD. Together with the enrollment of 49 phosphatases and 272 protein kinases, results suggest the involvement of ABA-signaling processes in drought acclimation. The integration of these findings with complementing physiological and biochemical studies reveals that both genotypes are more resilient to moderate drought than previously thought and suggests the existence of post-transcriptional mechanisms modulating the response to drought.