Plant-pathogen interactions are a critical aspect of plant biology, reflecting the ongoing evolutionary battle between plants and the various pathogens that threaten them, including fungi, bacteria, viruses, nematodes, and oomycetes. To survive, plants have developed a diverse array of defense mechanisms, ranging from pre-formed structural barriers to complex molecular and cellular responses that are activated upon pathogen attack. This review provides a comprehensive overview of these defense strategies, including the role of pre-formed and induced structural defenses, chemical defenses, and the intricate signaling pathways that regulate these responses. Additionally, we examine the mechanisms underlying disease resistance, such as gene-for-gene resistance, quantitative resistance, systemic acquired resistance (SAR), and induced systemic resistance (ISR). The review also highlights recent advances in genetic engineering techniques, such as CRISPR/Cas9, transgenic approaches, and RNA interference, which are being used to enhance disease resistance in crops. Understanding these defense mechanisms and leveraging modern biotechnological tools are essential for developing more resilient crops and ensuring global food security in the face of ever-evolving pathogen threats.