The fungus Zymoseptoria tritici causes septoria tritici blotch (STB) on wheat, an important disease globally and the most damaging wheat disease in Europe. Despite the global significance of STB, the molecular basis of wheat defense against Z. tritici is poorly understood. Here, we use a comparative transcriptomic study to investigate how wheat responds to infection by four distinct strains of Z. tritici. We examined the response of wheat across the entire infection cycle, identifying both shared responses to the four strains and strain-specific responses. We found that the early asymptomatic phase is characterized by strong upregulation of genes encoding receptor-like kinases and pathogenesis-related proteins, indicating the onset of a defense response. We also identified genes that were differentially expressed among the four fungal strains, including genes related to defense. Genes involved in senescence were induced during both the asymptomatic phase and at late stages of infection, suggesting manipulation of senescence processes by both the plant and the pathogen. Our findings illustrate the need, when identifying important genes affecting disease resistance in plants, to include multiple pathogen strains.