Recent preclinical data have demonstrated that pancreatic adenocarcinoma (PDA) cells with defects in the Fanconi anemia/BRCA2 pathway are hypersensitive to interstrand crosslinking agents. The challenge is to efficiently identify patients who will benefit from these therapies. Patients were chosen for this study by evaluating personal history, ethnic background and family history of pancreatic malignancy. Molecular assays were performed on tissue samples. Patient A developed PDA in the context of a known BRCA2 frameshift mutation (2157delG), suspected because of her personal and multigenerational family history of breast cancer. She was treated with surgical resection, and targeted chemotherapy. Patient A continues to be disease free 32 months after her diagnosis and treatment. Patient B developed PDA in the context of a strong family history of PDA and Ashkenazi Jewish heritage. Genetic analysis on critical DNA repair genes revealed no alterations. This patient did not receive a tailored treatment regimen. This study highlights the challenge of treating PDA patients and selecting those eligible for targeted therapy. The current targeted treatment options for PDA are reviewed. A new multidisciplinary approach for stratifying PDA patients for promising targeted adjuvant therapy and familial risk counseling is proposed.