The South American Leaf Blight (SALB), due to the Ascomycota Microcyclus ulei, threatens the world production of natural rubber, based on the cultivation of nearly only one species: the tropical tree Hevea brasiliensis. In connection with a breeding program, conducted in Brazil by Michelin and Cirad and aiming to create resistant cultivars of rubber tree, the genetic determinism of three sources of natural resistance to SALB has been analyzed. We developed a classical approach of QTL mapping on a segregating population issued from a crosses implying a quantitative and durable resistant in MDF180 genotype (Le Guen et al., 2008), a quantitative and by-passed resistant in Fx3899 genotype, and a qualitative resistance in Fx2784 genotype. Disease resistance of the progenies was assessed under natural infestation in field trials, in Brazil and French Guyana, or under controlled inoculations with isolated strains of Microcyclus ulei. Genetic mapping revealed unexpected genetic determinisms underlying the observed resistances: whereas a complex genetic determinism implying major resistance genes and several minor QTLs can be bypassed by the pathogen (Le Guen et al. 2007), a durable partial resistance appeared to be governed by only 2 major resistance loci (Le Guen et al. 2011). To initiate a comprehensive approach of these resistances, eleven cDNA libraries were built, sequenced and annotated from MDF180, Fx3899, PB314 (susceptible) and PB260 (susceptible) genotypes (Garcia et al., 2011). We sequenced 20,493 expressed sequence tags (EST), developed array expression analysis and identified of 212 candidate genes differentially regulated in MDF180 and 30 genes in Fx3899 during the infection process. The integrated analysis of gene expression and systems biology allowed designing a general scheme of major mechanisms associated with durable resistance of MDF180 genotype and susceptibility of PB314 genotype to South American leaf blight. Concomitantly, transcriptomic NGS data gi