Pancreatic and liver cancers often have poor prognoses. Clinically, pancreatic and liver cancer requires early diagnosis, and surgery is often associated with tumor recurrence. Currently, chemotherapies are limited in their ability to accurately target the tumors, and are associated with significant toxicity in patients. Targeting of chemotherapy can be improved by encapsulation in nanocarriers. A variety of preclinical studies indicate relatively superior therapeutic outcomes compared with drug alone therapy. Targeted nanoparticle imaging agents may also additionally facilitate better diagnosis and improve patient outcomes. This review discusses the nanoformulations that are under investigation (mainly preclinical studies, but also with some current clinical trial examples) against pancreatic and liver cancers, understands the challenges and provides future perspectives.