Fusarium circinatum, causing pine pitch canker (PPC), affects conifers productivity and health worldwide. Selection and breeding for resistance arises as the most promising approach to fight PPC. Therefore, it is crucial to explore the response of hosts with varying levels of susceptibility to PPC to unveil the genes/pathways behind these phenotypes. We evaluated the dynamics of the needle proteome of a susceptible (Pinus radiata) and a relatively resistant (Pinus pinea) species upon F. circinatum inoculation by GeLC-MS/MS. Integration with physiological data and validation of key genes by qPCR allowed to identify core pathways regulating these contrasting responses. In P. radiata, the pathogen may target both the secondary metabolism to negatively regulate immune response and chloroplast redox proteins to increase energy-producing pathways for amino acid production in its favour. In contrast, chloroplast redox regulation may assure redox homeostasis in P. pinea, as well as nonenzymatic antioxidants. The presence of membrane trafficking-related proteins exclusively in P. pinea likely explains its defence response against F. circinatum. A crosstalk between abscisic acid and epigenetic regulation of gene expression is also proposed in PPC response. These results are useful to support breeding programs aiming to achieve PPC resistance.