The outcome of infection of individual plants by pathogenic organisms is governed by complex interactions between the host and pathogen. These interactions are the result of long-term co-evolutionary processes involving selection and counterselection between plants and their pathogens. These processes are ongoing, and occur at many spatio-temporal scales, including genes and gene products, cellular interactions within host individuals, and the dynamics of host and pathogen populations. However, there are few systems in which host–pathogen interactions have been studied across these broad scales. In this review, we focus on research to elucidate the structure and function of plant resistance and pathogen virulence genes in the flax-flax rust interaction, and also highlight complementary co-evolutionary studies of a related wild plant–pathogen interaction. The confluence of these approaches is beginning to shed new light on host–pathogen molecular co-evolution in natural environments.