Defining the minimal protein determinants of enzymic reactions, biological interactions, and immune recognition is at the core of biochemistry, pathology and therapeutics. Indeed, short peptide sequences are involved in physiological processes such as cell growth and apoptosis, and in pathological phenomena such as amyloid protein fibrillogenesis and tumor cell migration. An active peptide may exert more powerful activity than the entire parent protein and, in immunology, use of short peptides may improve immunotherapies and avoid the potential hazards of using full-length protein antigens. This review illustrates the concept that a peptide sequence only 5-residues long may be used as a basic functional unit in cell biology and immunology, underlines the crucial biological roles played by minisequences and emphasizes the multifold applications of short peptides as therapeutic agents.