The immune system operates through tightly regulated activation and restraint to protect the host while limiting collateral tissue injury. When immune regulation becomes maladaptive, it contributes to diverse diseases spanning autoimmunity, chronic inflammation, cancer, infection, and transplantation. Immunomodulators have therefore become central therapeutic tools that tune immune pathways and cellular circuits to achieve disease-appropriate immune control. This review provides an updated, mechanism-to-clinic synthesis of immunomodulatory strategies, integrating cytokine-targeted biologics, small-molecule kinase inhibitors, checkpoint modulation, tolerance-oriented approaches, cell-based therapies, and emerging platforms including mRNA/nanomedicine and microbiome-targeted interventions. Beyond description, we critically evaluate key limitations—heterogeneous response, pathway redundancy, immunogenicity, and safety trade-offs—and highlight how biomarker-guided stratification and systems-level immune profiling can improve therapeutic matching. Finally, we discuss future directions toward antigen-specific, temporally controllable, and risk-adaptive immunomodulation.