Antimicrobial peptides (AMPs) are evolutionarily ancient, structurally diverse molecules that form a critical first line of innate immune defense across all domains of life. In humans, AMPs include the α- and β-defensin families, the cathelicidin LL-37, histatins, dermcidin, granulysin, and numerous other endogenous host defense peptides, collectively constituting a sophisticated multimodal system capable of direct microbicidal activity, immunomodulation, and barrier maintenance. This evidence-based narrative review addresses four interconnected dimensions of AMP biology relevant to the clinician and researcher. First, the structural classification of human AMPs, their cellular sources, and mechanisms of action are reviewed, encompassing membrane-disruptive models (barrel-stave, toroidal pore, carpet), cell wall synthesis inhibition (lipid II targeting), intracellular targeting, and immunomodulatory mechanisms. Second, the expanding roles of AMPs beyond direct killing are discussed — including chemotaxis, toll-like receptor (TLR) modulation, wound healing, angiogenesis, and the bridging of innate and adaptive immunity. Third, the bidirectional relationships between AMP dysregulation and human disease are examined across eight clinical conditions: atopic dermatitis, psoriasis, Crohn's disease, sepsis, COVID-19 and respiratory infections, systemic lupus erythematosus, rosacea, and cancer. Fourth, the clinical translation pipeline is reviewed for ten AMPs currently approved, in late-stage trials, or recently completing Phase II/III development — including polymyxin B/colistin, daptomycin, rezafungin (FDA-approved 2023), omiganan, pexiganan, brilacidin, LL-37, NP213 (novexatin), murepavadin, and DPK-060. The current challenges to clinical translation — protease susceptibility, cytotoxicity, bioavailability, manufacturing cost — and the emerging solutions including D-amino acid substitution, peptide-mimetics, nanoparticle encapsulation, and AI-driven AMP discovery are also reviewed. The global burden of antimicrobial resistance (AMR), responsible for an estimated 4.9 million attributable deaths in 2019, makes the clinical development of AMP-based therapeutics a scientific and public health imperative.