What makes a peptide an epitope? This is a central question in immunology. The clear identification of precise molecular characteristics of epitopes would help define the basic mechanisms of self/non-self distinction and lead to a greater understanding of phenomena such as tolerance, autoimmunity, allergy, and tumor escape of immune surveillance. Importantly, clarifying the properties an epitope is paramount to the development of diagnostic and therapeutic vaccines. This review analyzes recent reports on experimentally identified B cell epitopes associated with multiple infectious disease pathologies, cancer, autoimmunity, hypertension, obesity, and allergy. It illustrates data that further support the notion that only a low level of sequence similarity to the host proteome is needed to modulate the B cell epitope-specific peptidome. Amino acid sequences that are unique to the antigen and are not shared with the host proteome are specifically targeted by the humoral immune response. Therefore, low-similarity peptides may be significant to the rational development of peptide-based clinical treatments in cancer, autoimmunity, infection, and allergy. Biologically, the lowsimilarity hypothesis further supports sequence uniqueness as the molecular signature of “ nonselfness ” in the currently ongoing self/non-self debate.