During their life cycle, plants are exposed to microbes in soil and leaf surfaces that can cause disease and result in crop losses and pathogen spread. Even though chemical treatment and genetic engineering have been successfully applied to combat disease, it is increasingly being recognized that understanding the natural co-evolution of plants with pathogens will provide new leads for pest regulation and, potentially, anticipate evolving pathogen strategies to evade recognition and cause disease. This new perspective requires understanding fundamental questions in the co-evolution between plants and pathogens using a combined genetic and molecular approach, and studying natural populations of plants that may be locally adapted. During the co-evolution with pathogens, plants have evolved mechanisms to distinguish foe from a benign or potentially beneficial microorganism and to induce appropriate defense reactions and anti-microbial molecules. However, activation of pathogen defense is likely costly for the plant as evidenced in growth defects exhibited by plants with constitutive activation of immune responses. As consequence, a proper balance between growth, reproduction and immune response had to be achieved during evolution, leading to an inducible immune system influenced by environmental fluctuations. The recent discovery of temperature-dependent hybrid incompatibilities in Arabidopsis thaliana allows at identifying genetic components at the intersection between plant immunity and the environment. Studying the molecular and genetic basis for such incompatibilities should provide novel insights into mechanisms underlying temperature regulation of plant immunity and local adaptation shaping genetic variation of immune-related genes.