Breeding for disease resistance is an essential strategy in agriculture, aimed at enhancing the resilience of crops and livestock against various pathogens. This chapter explores the intricate molecular basis underlying disease resistance, highlighting the genetic mechanisms that enable plants to detect and respond to infections. We discuss the two primary types of resistance: qualitative and quantitative, detailing how resistance genes (R genes) and multiple quantitative trait loci (QTL) play critical roles in defense responses. The chapter delves into key biochemical mechanisms, such as pathogen-associated molecular pattern (PAMP) recognition and effector-triggered immunity (ETI), which activate the plant immune system. Additionally, we examine the significance of secondary metabolites in bolstering resistance. Advancements in molecular markers and genomic technologies have revolutionized breeding practices, facilitating marker-assisted selection (MAS) that streamlines the identification of resistant varieties. We also highlight the transformative impact of biotechnology, including genetic engineering and genome editing techniques like CRISPR-Cas9, in developing robust disease-resistant crops. Despite these advancements, challenges remain, such as pathogen evolution, regulatory hurdles, and public perception of genetically modified organisms (GMOs). This chapter emphasizes the need for ongoing research and collaboration among scientists, farmers, and policymakers to navigate these challenges and promote sustainable agricultural practices. Understanding disease resistance's molecular basis enhances breeding efforts and contributes to global food security and environmental sustainability.