Crop plants are exposed in nature to various biotic and abiotic stresses they significantly influence survival and productivity. Multiple transcriptional reprogramming takes place in a plant to overcome these stresses by activation of defense-related genes. The defense-related gene expression results in the production of pathogenesis-related (PR) proteins, phytoalexins, Reactive oxygen species (ROS) and other related enzymes. Transcription factors (TFs) play a significant role in the activation of defense in a plant against fungal, viral, and bacterial infection. Several TFs such as AP2/ERF, bHLH, WRKY, bZIP, MYC, MYB, NAM, and NAC are involved during plant-pathogen interaction. Among several TFs, WRKY TFs represent a maximum number of regulatory proteins that regulate the downstream activation of defense genes through direct or indirect mechanisms. Here, we are discussing on recent progress in understanding the structure and function of WRKY TFs and how they are regulated and interacted with other related TFs to confer disease resistance in plants. We also discussed important WRKY TFs involved during viral, bacterial, and fungal pathogen infection that are regulated in a positive or negative way to decide whether the plant will be resistant or susceptible. Protein-DNA identification techniques and recent advances including proteomics, metabolomics and interactomics are important to identify the function and reveal complex transcriptional factor networks of TFs. Their roles and relative knowledge will help in engineering pathogen resistance in crop plants.