Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, with a 5-year survival rate of 6% and rising incidence linked to obesity and metabolic syndrome. The high mortality rate is due to late diagnosis and ineffective treatments. Recent advances in genomics, preclinical models, and molecular classification have improved drug discovery and clinical hypotheses. Understanding cancer cell metabolism and DNA repair has led to novel therapeutic strategies. Immune regulation in the tumor microenvironment is also being explored to enhance immune responses against PDAC. PDAC arises from precursor lesions like PanINs, which progress to invasive cancer. PanINs are classified into low-grade (PanIN-1/2) and high-grade (PanIN-3), with PanIN-3 being more aggressive. These lesions are critical for early detection and prevention. Studies show that oncogenic Kras expression in various pancreatic cell types can lead to PDAC, with acinar-to-ductal metaplasia (ADM) playing a role in some cases. However, the human relevance of ADM to PDAC is unclear. Genomic studies reveal that PDAC is characterized by numerous mutations, including frequent inactivation of tumor suppressors like TP53, SMAD4, and CDKN2A. Mutations in epigenetic regulators, such as MLL, KDM6A, and SWI/SNF complexes, are also common. These mutations affect chromatin remodeling and DNA repair, contributing to tumor progression. The NOTCH, Hedgehog, and Wnt pathways are also involved in PDAC development. The DDR pathway is crucial for PDAC, with mutations in genes like BRCA1, BRCA2, and PALB2 increasing cancer risk. These mutations lead to genomic instability and poor prognosis. DDR defects can be targeted with PARP inhibitors, but their effectiveness varies. Mutations in the PI3K pathway, including PIK3CA and AKT1, are common in IPMN-associated PDAC and are linked to poor outcomes. KRAS is the most common oncogenic driver in PDAC, with mutations in G12D or G12V being prevalent. However, different KRAS mutations have distinct biological effects. KRAS signaling is mediated through pathways like RAF/MEK/MAPK, PI3K/PTEN/AKT, and RAL-GDS. These pathways are critical for tumor growth and maintenance. Targeting KRAS directly is challenging, but strategies like targeting its farnesylation or using small molecule inhibitors are being explored. KRAS-independent resistance mechanisms, such as YAP1 activation and RTK pathway activation, are emerging. These mechanisms allow PDAC cells to survive despite KRAS inhibition. Understanding these mechanisms is crucial for developing effective therapies. PDAC metabolism is also a key area of research, with enhanced glycolysis and glucose metabolism playing a role in tumor growth. Targeting metabolic pathways, suchPancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, with a 5-year survival rate of 6% and rising incidence linked to obesity and metabolic syndrome. The high mortality rate is due to late diagnosis and ineffective treatments. Recent advances in genomics, preclinical models, and molecular classification have improved drug discovery and clinical hypotheses. Understanding cancer cell metabolism and DNA repair has led to novel therapeutic strategies. Immune regulation in the tumor microenvironment is also being explored to enhance immune responses against PDAC. PDAC arises from precursor lesions like PanINs, which progress to invasive cancer. PanINs are classified into low-grade (PanIN-1/2) and high-grade (PanIN-3), with PanIN-3 being more aggressive. These lesions are critical for early detection and prevention. Studies show that oncogenic Kras expression in various pancreatic cell types can lead to PDAC, with acinar-to-ductal metaplasia (ADM) playing a role in some cases. However, the human relevance of ADM to PDAC is unclear. Genomic studies reveal that PDAC is characterized by numerous mutations, including frequent inactivation of tumor suppressors like TP53, SMAD4, and CDKN2A. Mutations in epigenetic regulators, such as MLL, KDM6A, and SWI/SNF complexes, are also common. These mutations affect chromatin remodeling and DNA repair, contributing to tumor progression. The NOTCH, Hedgehog, and Wnt pathways are also involved in PDAC development. The DDR pathway is crucial for PDAC, with mutations in genes like BRCA1, BRCA2, and PALB2 increasing cancer risk. These mutations lead to genomic instability and poor prognosis. DDR defects can be targeted with PARP inhibitors, but their effectiveness varies. Mutations in the PI3K pathway, including PIK3CA and AKT1, are common in IPMN-associated PDAC and are linked to poor outcomes. KRAS is the most common oncogenic driver in PDAC, with mutations in G12D or G12V being prevalent. However, different KRAS mutations have distinct biological effects. KRAS signaling is mediated through pathways like RAF/MEK/MAPK, PI3K/PTEN/AKT, and RAL-GDS. These pathways are critical for tumor growth and maintenance. Targeting KRAS directly is challenging, but strategies like targeting its farnesylation or using small molecule inhibitors are being explored. KRAS-independent resistance mechanisms, such as YAP1 activation and RTK pathway activation, are emerging. These mechanisms allow PDAC cells to survive despite KRAS inhibition. Understanding these mechanisms is crucial for developing effective therapies. PDAC metabolism is also a key area of research, with enhanced glycolysis and glucose metabolism playing a role in tumor growth. Targeting metabolic pathways, such