Biotic and abiotic stresses are predicted to be the main drivers of forest tree decline and mortality in a climatic change scenario. It occurs, for example, in Quercus ilex, the main component of the Mediterranean forest, becoming a major environmental, economic and social concern. The decline syndrome is the result of factors interrelated in time and space. Breeding, through variability and elite genotype selection, is the only plausible strategy for forest management and conservation in nondomesticated, orphan species as is the case of the genus Quercus. By using a shotgun proteomics approach, the effect and the responses to combined drought stress and pathogen (Phytophthora cinnamomi) have been analyzed in two Holm oak populations with contrasting responses to each individual stress. Proteomics data are correlated with that of plant survival, damage symptoms, leaf chemical composition and physiological phenotypes (water content and photosynthetic activity). Changes in the protein profile depended on the population, stress, and time, with some consistent upaccumulated proteins related to synthesis, primary and secondary metabolism, and cell wall are discussed.