Fish immunology is a rapidly evolving field that plays a crucial role in understanding disease resistance mechanisms and improving aquaculture health. Functional genomics, encompassing high-throughput sequencing technologies, transcriptomics, proteomics, metabolomics, and gene-editing tools like CRISPR-Cas9, has revolutionized the study of immune responses in fish. This review provides a comprehensive overview of fish immunology, highlighting the innate and adaptive immune systems, key immune cells and organs, and major pathogens affecting fish species. The application of functional genomics has facilitated the identification of immune-related genes, elucidated host–pathogen interactions, and enabled gene expression profiling under pathogenic stress. Comparative genomic studies have provided evolutionary insights into immune gene families and their adaptive evolution. The role of epigenetics in immune regulation, including DNA methylation and histone modifications, is also explored, emphasizing the impact of environmental factors on immune responses. Furthermore, case studies demonstrate the effectiveness of functional genomics in analyzing bacterial, viral, and parasitic infections in fish. Despite remarkable advancements, challenges such as technical limitations and the integration of multi-omics data persist.