Broad-spectrum resistance to Melampsora larici-populina (Mlp) leaf rust is a major challenge for poplar breeding in Northern Europe. When no rust epidemic was evident in the natural Populus nigra populations, cultivation of inter-specific clones carrying qualitative resistances have strongly modified both qualitative and quantitative pathogenicity components of Mlp populations in cultivated areas. In monoclonal poplar plantations, durability of rust resistance will depend strongly on (1) resistance mechanisms pyramided in a given genotype, (2) genetic diversity present in Mlp populations submitted to these high selection pressures and (3) possibility of recombination rate associated with sexual reproduction on larch. Recent results on genetic and molecular bases of Mlp-poplar interaction and multidisciplinary research projects in development will be presented. Although quantitative resistance (QR) is often considered more durable, a multidisciplinary approach is being conducted at INRA not only to identify optimal genetic constructions for broad spectrum resistance but also to predict potential adaptation of the pathogen. Starting with a single Populus deltoides x P. trichocarpa F1 pedigree, much attention is being paid to two major loci, R1 and RUS, that both map on LG XIX. Dominant allele R1 is inherited from P. deltoides. It controls a qualitative resistance to M. larici-populina, and it was found to be statistically associated with QR levels in several P. deltoides x P. trichocarpa F1 progenies. Dominant allele RUS is inherited from P. trichocarpa. It has major effect of uredinia size and other QR components in both intraspecific and interspecific F1 progenies. Fine mapping of RUS is being conducted using a 1410 genotype F1 host progeny, and a BAC library was constructed to generate a physical map of 2000 kb around RUS. A promising BAC clone has been identified and sequenced. In parallel, an expressional approach based on the analysis of RUS and rUS infected material generated transcriptional and translational candidates. Opportunities offered by genetic variability available in Populus nigra, the natural host of Mlp, are currently explored in inter-specific crosses and in a new F1 mapping pedigree. Moreover, a collection of more than 1100 P.nigra genotypes collected in different natural European populations has been recently evaluated for rust resistance to initiate an association genetic study. On the pathogen side, several populations of M. larici-populina that underwent contrasted selection pressures by RUS are being characterized for their phenotypes and for their genotypes at several microsatellite loci. The first results demonstrate the existence of preadaptation in “wild” pathogen populations and a clear selective pressure by the host. All these results will be discussed in the framework of poplar breeding strategies and poplar cultivar deployment.