Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of only 6%, driven by the lack of early diagnosis and ineffective treatment for advanced stages. Recent advancements in genomics, preclinical model systems, and molecular classification have advanced drug discovery and clinical hypotheses. Understanding cancer cell biology, particularly altered metabolism and impaired DNA repair, has led to novel therapeutic strategies. The complexity of immune regulation in the tumor microenvironment offers new avenues for immune system reawakening to attack PDAC cells. The path to meaningful clinical progress is clear, but translation remains a challenge. PDAC presents as a poorly demarcated, firm white-yellow mass, with surrounding atrophic and fibrotic pancreas. Microscopically, these neoplasms vary from well-differentiated to poorly differentiated carcinomas. PDAC evolves from precursor lesions, including microscopic pancreatic intraepithelial neoplasia (PanIN) and macroscopic cysts like intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). High-grade PanIN3 lesions are almost exclusively found in invasive PDAC. The identification of these precursor lesions has provided a framework for early detection and targeted therapeutics. Next-generation sequencing has revealed a complex landscape of genetic alterations in PDAC, including frequent mutations in *KRAS*, *TP53*, *SMAD4*, and *CDKN2A*. Additional recurrent mutations in pathways like NOTCH, Hedgehog, β-catenin, and DNA repair highlight key therapeutic targets. Epigenetic regulators, such as histone modification enzymes and SWI/SNF complexes, are also frequently mutated, suggesting their importance in PDAC pathogenesis. DDR pathway mutations are common, with BRCA1 and BRCA2 mutations being particularly significant, leading to genomic instability and poor prognosis. PDAC exhibits focal amplifications of oncogenes like *MYC* and *ROK3*, and receptor tyrosine kinases like *ERBB2*, *EGFR*, *MET*, and *IGFR1*. The *KRAS* oncogene is a prime therapeutic target, but its signaling network is complex, involving RAF/MEK/MAPK, PI3K/PTEN/AKT, and RAL-GDS pathways. Targeting these pathways has shown limited success, highlighting the need for more effective strategies. PDAC cells reprogram their metabolism to support proliferation, with enhanced glycolysis and lactate production. Oncogenic *KRAS* plays a crucial role in rewiring glucose metabolism, promoting anabolic processes. Targeting these metabolic pathways may provide therapeutic vulnerabilities. PDAC's high mortality rate stems from the lack of early diagnosis and ineffective treatments. Recent advancements in genomics and preclinical models have advanced drug discovery and clinical hypotheses. Understanding cancer cell biology, particularly altered metabolism and DNA repair, has ledPancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of only 6%, driven by the lack of early diagnosis and ineffective treatment for advanced stages. Recent advancements in genomics, preclinical model systems, and molecular classification have advanced drug discovery and clinical hypotheses. Understanding cancer cell biology, particularly altered metabolism and impaired DNA repair, has led to novel therapeutic strategies. The complexity of immune regulation in the tumor microenvironment offers new avenues for immune system reawakening to attack PDAC cells. The path to meaningful clinical progress is clear, but translation remains a challenge. PDAC presents as a poorly demarcated, firm white-yellow mass, with surrounding atrophic and fibrotic pancreas. Microscopically, these neoplasms vary from well-differentiated to poorly differentiated carcinomas. PDAC evolves from precursor lesions, including microscopic pancreatic intraepithelial neoplasia (PanIN) and macroscopic cysts like intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs). High-grade PanIN3 lesions are almost exclusively found in invasive PDAC. The identification of these precursor lesions has provided a framework for early detection and targeted therapeutics. Next-generation sequencing has revealed a complex landscape of genetic alterations in PDAC, including frequent mutations in *KRAS*, *TP53*, *SMAD4*, and *CDKN2A*. Additional recurrent mutations in pathways like NOTCH, Hedgehog, β-catenin, and DNA repair highlight key therapeutic targets. Epigenetic regulators, such as histone modification enzymes and SWI/SNF complexes, are also frequently mutated, suggesting their importance in PDAC pathogenesis. DDR pathway mutations are common, with BRCA1 and BRCA2 mutations being particularly significant, leading to genomic instability and poor prognosis. PDAC exhibits focal amplifications of oncogenes like *MYC* and *ROK3*, and receptor tyrosine kinases like *ERBB2*, *EGFR*, *MET*, and *IGFR1*. The *KRAS* oncogene is a prime therapeutic target, but its signaling network is complex, involving RAF/MEK/MAPK, PI3K/PTEN/AKT, and RAL-GDS pathways. Targeting these pathways has shown limited success, highlighting the need for more effective strategies. PDAC cells reprogram their metabolism to support proliferation, with enhanced glycolysis and lactate production. Oncogenic *KRAS* plays a crucial role in rewiring glucose metabolism, promoting anabolic processes. Targeting these metabolic pathways may provide therapeutic vulnerabilities. PDAC's high mortality rate stems from the lack of early diagnosis and ineffective treatments. Recent advancements in genomics and preclinical models have advanced drug discovery and clinical hypotheses. Understanding cancer cell biology, particularly altered metabolism and DNA repair, has led