Arabica coffee is a main economic crop throughout Central and South American highlands, where millions of people get primary outcome. Last coffee leaf rust (CLR) epidemic event in 2011, which impacted 53% of the coffee region areas, provoking losses up to USD 500 million, remembered the high vulnerability of the coffee sector to the fungus Hemileia vastatrix, causal agent of this disease and considered as the main restrictive illness for all coffee regions around the world. The main problem remains that the current commercial varieties reputed as "resistant", become sensitive to the CLR. During the last twenty years, coffee geneticist have created several intra-specific hybrids between commercial varieties and wild coffee accessions. Field observations confirmed that coffee hybrids are more productive and less impacted by the CLR even in regions where resistant materials become susceptible. Such field observations are in agreement with the general idea that hybrid plants present high homeostasis in terms of growth, yield and disease resistance. The aim of this research was to investigate the physiological response of coffee hybrids before and after inoculation with the CLR. Using controlled conditions, the metabolic response and physiological status of two hybrid genotypes were assessed under different stressful conditions involving three limiting factors: temperature, luminosity and nitrogen input. Hybrid behavior was compared to an inbred line tested under similar conditions. Results demonstrated that whatever the agronomic conditions and the temperature regimes, hybrids under test were less sensitive to CLR than the inbred line. Interestingly, the detailed transcriptomic analysis revealed that coffee hybrids seem to exhibit an altered circadian clock resulting in a higher photosynthetic efficiency together with an increased concentration of chlorophyll. Most of the over-expressed genes identified in the hybrids after CLR inoculation were associated to basal resis