Pancreatic ductal adenocarcinoma (PDAC) is a common and aggressive cancer, with approximately 60,430 new cases expected in the US in 2021. Its incidence is increasing, and it is projected to become the second-leading cause of cancer-related mortality by 2030. PDAC is the third-leading cause of cancer mortality in the US and the seventh in the world. Most patients present with advanced disease, with 50% having metastatic disease at diagnosis. Effective screening is not available, and the 5-year survival rate has increased slightly, but treatment options remain limited. Current cytotoxic therapies are modestly effective, and multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended for all patients. PDAC is associated with various risk factors, including smoking, alcohol use, chronic pancreatitis, and obesity. Genetic factors also play a role, with pathogenic germline variants in genes such as BRCA1/2, ATM, and mismatch repair genes increasing susceptibility. Germline testing is recommended for all patients with PDAC, and a multigene panel is preferred over single-gene testing. The molecular pathogenesis of PDAC involves complex genetic alterations, including mutations in KRAS, CDKN2A, TP53, and SMAD4. These mutations contribute to tumor progression and resistance to therapy. Recent advances in molecular profiling have led to the identification of subtypes of PDAC, such as "basal-like" and "classical," which may influence treatment decisions. For localized PDAC, resectable disease is treated with surgery followed by adjuvant chemotherapy, typically FOLFIRINOX or gemcitabine. Neoadjuvant therapy with or without radiation is used for resectable and borderline resectable disease. For locally advanced and unresectable disease, systemic therapy followed by radiation is an option. For advanced PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, offer improved survival compared to single-agent gemcitabine. For patients with BRCA pathogenic germline variants and metastatic PDAC, olaparib is a maintenance option that improves progression-free survival. For metastatic PDAC, standard first-line treatments include gemcitabine and albumin-bound paclitaxel or modified FOLFIRINOX. The POLO trial validated the use of olaparib for patients with germline BRCA1/2 mutations, leading to FDA approval. Novel therapies, including immune checkpoint inhibitors and targeted agents, are being investigated for PDAC, particularly in patients with DNA damage repair gene alterations or mismatch repair deficiency. Symptom management and supportive care are essential for improving quality of life. Biliary and gastric obPancreatic ductal adenocarcinoma (PDAC) is a common and aggressive cancer, with approximately 60,430 new cases expected in the US in 2021. Its incidence is increasing, and it is projected to become the second-leading cause of cancer-related mortality by 2030. PDAC is the third-leading cause of cancer mortality in the US and the seventh in the world. Most patients present with advanced disease, with 50% having metastatic disease at diagnosis. Effective screening is not available, and the 5-year survival rate has increased slightly, but treatment options remain limited. Current cytotoxic therapies are modestly effective, and multidisciplinary management, comprehensive germline testing, and integrated supportive care are recommended for all patients. PDAC is associated with various risk factors, including smoking, alcohol use, chronic pancreatitis, and obesity. Genetic factors also play a role, with pathogenic germline variants in genes such as BRCA1/2, ATM, and mismatch repair genes increasing susceptibility. Germline testing is recommended for all patients with PDAC, and a multigene panel is preferred over single-gene testing. The molecular pathogenesis of PDAC involves complex genetic alterations, including mutations in KRAS, CDKN2A, TP53, and SMAD4. These mutations contribute to tumor progression and resistance to therapy. Recent advances in molecular profiling have led to the identification of subtypes of PDAC, such as "basal-like" and "classical," which may influence treatment decisions. For localized PDAC, resectable disease is treated with surgery followed by adjuvant chemotherapy, typically FOLFIRINOX or gemcitabine. Neoadjuvant therapy with or without radiation is used for resectable and borderline resectable disease. For locally advanced and unresectable disease, systemic therapy followed by radiation is an option. For advanced PDAC, multiagent chemotherapy regimens, including FOLFIRINOX, gemcitabine/nab-paclitaxel, and nanoliposomal irinotecan/fluorouracil, offer improved survival compared to single-agent gemcitabine. For patients with BRCA pathogenic germline variants and metastatic PDAC, olaparib is a maintenance option that improves progression-free survival. For metastatic PDAC, standard first-line treatments include gemcitabine and albumin-bound paclitaxel or modified FOLFIRINOX. The POLO trial validated the use of olaparib for patients with germline BRCA1/2 mutations, leading to FDA approval. Novel therapies, including immune checkpoint inhibitors and targeted agents, are being investigated for PDAC, particularly in patients with DNA damage repair gene alterations or mismatch repair deficiency. Symptom management and supportive care are essential for improving quality of life. Biliary and gastric ob