CD4 is a nonpolymorphic transmembrane glycoprotein molecule that is expressed on the surface of T-helper cells and plays an essential role in the immune response. It functions as a coreceptor with the T-cell receptor by binding to major histocompatibility complex class II on the surface of dendritic cells that present antigens. CD4+ T cells hold a key position in coordinating the immune system through production of several cytokines after activation and differentiation. The CD4+ T helper subtypes (T-helper 1, T-helper 2, T-helper 17, T-helper 9, and regulatory-T cells) perform different immune functions subsequent to their differentiation from the naive T cells. Different types of CD4+ T cells require different cytokines such as drivers and effectors, as well as master transcription factors for their activation. Fish cells that express CD4-related genes are activated in the presence of a pathogen and release cytokines against the pathogen. This review highlights the types of CD4+ T cells in fish and describes their direct role in cell-mediated and humoral immunity for protection against the intracellular bacterial as well as viral infections in fish.