Purpose <p>Pancreatic cancer exhibits high mortality due to its aggressive nature, late-stage detection, and dense desmoplastic stromal barriers that exclude larger biologics like monoclonal antibodies. This review explores the utility of peptides (~1–2 kDa) as molecular tools, given their unique capacity to bypass high interstitial fluid pressure and provide rapid tissue penetration, high specificity, and adaptability for diagnostic and therapeutic applications.</p> Methods <p>We evaluate contemporary peptide discovery platforms, including phage display, rational design, and “one-bead-one-compound” (OBOC) combinatorial libraries used to identify high-affinity ligands for tumor-associated markers. Additionally, the review investigates the emerging field of immunopeptidomics to identify cryptic (noncanonical) peptides derived from traditionally “noncoding” genomic regions.</p> Results <p>Peptide-based strategies yield significant diagnostic innovations, such as the GB-6 peptide targeting gastrin-releasing peptide receptors (GRPR) and pH-responsive probes that exploit the acidic tumor microenvironment for high-contrast imaging. Therapeutically, immunopeptidomics addresses the scarcity of classical neoantigens in pancreatic cancer—which typically has a low-to-intermediate mutational burden—by uncovering shared, cancer-restricted antigens. These noncanonical targets show strong translational potential for personalized TCR-redirected T cell therapies, demonstrating robust cytotoxicity against patient-derived organoids.</p> Conclusion <p>Despite hurdles related to in vivo metabolic stability and pharmacokinetics, peptide-based strategies offer a highly adaptable approach to overcoming the physical and immunological barriers of pancreatic cancer. The future of precision oncology in this domain relies on integrating multifunctional peptide-drug conjugates with noncanonical antigen targeting to achieve earlier detection and more effective, durable treatments.</p>