Septoria nodorum blotch (SNB) is an important disease affecting wheat in many of its production areas around the world, and is caused by the ascomycete fungal pathogen Parastagonospora nodorum. Breeding for SNB resistance has been hampered by the polygenic and quantitative nature of the resistance, and the farmers often have to rely on fungicides to control the disease. In recent years, substantial progress has been made in understanding the P. nodorum–wheat pathosystem. Several host-specific interactions between necrotrophic effectors (NEs) and host sensitivity (Snn) genes have been identified and play major roles in SNB seedling resistance. Some of the NEs have been cloned and can be used to screen breeding material at the seedling stage. This chapter provides an overview of the molecular understanding of host–pathogen interactions, progress in understanding the genetics of host resistance and use of molecular markers and effector screening as promising tools in resistance breeding for this challenging disease.