Immunosuppressive drugs comprise a diverse arsenal of biologic agents and small-molecule therapies used to treat autoimmune, inflammatory, and transplant-related conditions. Classes include anti–tumor necrosis factor (TNF) agents, interleukin inhibitors (IL-12/23, IL-17, IL-1), Janus kinase (JAK) inhibitors, calcineurin inhibitors, mTOR inhibitors, and systemic glucocorticoids. Each class targets distinct pathways—TNF-α signaling, cytokine-receptor interactions, JAK–STAT transduction, calcineurin–NFAT activation, mTOR complexes, and glucocorticoid receptor–mediated transcription—with resulting immunomodulation. Pharmacokinetic properties vary by route of administration and depend on gastrointestinal absorption, first-pass metabolism, and therapeutic drug monitoring, especially in patients with altered gut anatomy or active inflammation. Adverse effects span infection risk, paradoxical inflammatory flares, hepatotoxicity, nephrotoxicity, gastrointestinal ulceration, metabolic derangements, and cytopenias. Clinicians must integrate mechanistic insights, safety profiles, and absorption considerations to personalize therapy selection, dosing, and monitoring. This chapter reviews the mechanisms of action, gastrointestinal absorption issues, and side-effect profiles of major immunosuppressive drug classes, providing a practical framework for optimizing treatment in rheumatologic, gastroenterologic, and transplant populations.