Biotic stresses, predominantly caused by pathogens, pose significant threats to global crop production. Despite the prevalent use of pesticides, their adverse environmental and economic impacts highlight the requirement for alternative approaches such as breeding for host plant resistance. This chapter comprehensively examines the molecular mechanisms of disease resistance, including structural defenses, antimicrobial compounds, hormonal signaling, and inducible responses. It explores various breeding strategies from conventional methods to advanced biotechnological approaches like genetic engineering and genomic selection aimed at developing disease resistant cultivars. Critical challenges such as pathogen diversity, environmental interactions, complex genetics, and the impacts of climate change are addressed. The study emphasizes the importance of collaborative efforts among farmers, researchers, and breeders to enhance crop resilience and to safeguard global food security in the face of evolving agricultural challenges.