Pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly more common. Treatment for PDAC is dependent not only on stage at diagnosis, but complex anatomical relationships. Recently, the therapeutic approach to this disease has shifted from upfront surgery for technically resectable lesions to a neoadjuvant therapy first approach. Selecting an appropriate regimen and determining treatment response is crucial for optimal oncologic outcome, especially since radiographic imaging has proven unreliable in this setting. Tumor biomarkers have the potential to play a key role in treatment planning, treatment monitoring, and surveillance as an adjunct laboratory test. In this review, we will discuss common chemotherapeutic options, mechanisms of resistance, and potential biomarkers for PDAC. The aim of this paper is to present currently available biomarkers for PDAC and to discuss how these markers may be affected by neoadjuvant chemotherapy treatment. Understanding current chemotherapy regiments and mechanism of resistance can help us understand which markers may be most affected and why; therefore, determining to what ability we can use them as a marker for treatment progression, prognosis, or potential relapse.