The range of hosts that a pathogen can infect is a major determinant of disease epidemics. This trait is highly dynamic and constrained by pathogen genetics, host genetics, and environmental constraints. A single modern strain of the white mold fungus Sclerotinia sclerotiorum can infect hundreds of plant species, resulting in a major threat to oil and vegetable crops. S. sclerotiorum evolved through host range expansion: it readily infects plants of the Brassicaceae family while the closely related S. trifoliorum cannot. Comparative genomics, transcriptomics, and pangenome analyses indicated that the colonization of Arabidopsis plants associates with responsiveness of a S. sclerotiorum transcription factor to the Brassicaceae defense metabolite camalexin. On the plant side, genes conserved across six botanical families were enriched with genes differentially expressed upon challenge by S. sclerotiorum. However only 2% of these core genes showed a consistent expression pattern across all plant species, pointing toward frequent regulatory variation. Using association genomics, we identified A. thaliana conserved genes recruited into resistance to S. sclerotiorum through regulatory variation at the infraspecific level. These findings point towards regulatory exaptation as a prominent evolutionary scenario shaping the molecular interactions between plants and generalist pathogens. Implications on the genetic bases of adaptability and on the design of pathogen management strategies will be discussed