The article reviews the current understanding and future strategies for targeting KRAS mutations in pancreatic cancer. KRAS, a key protein in signaling pathways, is frequently mutated in pancreatic ductal adenocarcinoma (PDAC), making it a therapeutic target. The article highlights the challenges in developing effective treatments due to the high affinity of KRAS for GTP and the lack of suitable binding pockets for small molecule inhibitors. Recent advancements include the discovery of covalent KRASG12C inhibitors and other investigational agents. However, resistance mechanisms, such as secondary mutations and bypass signaling pathways, have been documented. The article discusses combination therapies, including upstream and downstream inhibitors, immunotherapy, and other agents, to overcome resistance and improve outcomes. It also explores novel strategies like KRAS degraders, siRNA, adoptive cell therapy, and cancer vaccines. The authors emphasize the need for a comprehensive understanding of KRAS mutational profiles, metabolic needs, and the tumor microenvironment to develop optimal treatment approaches.The article reviews the current understanding and future strategies for targeting KRAS mutations in pancreatic cancer. KRAS, a key protein in signaling pathways, is frequently mutated in pancreatic ductal adenocarcinoma (PDAC), making it a therapeutic target. The article highlights the challenges in developing effective treatments due to the high affinity of KRAS for GTP and the lack of suitable binding pockets for small molecule inhibitors. Recent advancements include the discovery of covalent KRASG12C inhibitors and other investigational agents. However, resistance mechanisms, such as secondary mutations and bypass signaling pathways, have been documented. The article discusses combination therapies, including upstream and downstream inhibitors, immunotherapy, and other agents, to overcome resistance and improve outcomes. It also explores novel strategies like KRAS degraders, siRNA, adoptive cell therapy, and cancer vaccines. The authors emphasize the need for a comprehensive understanding of KRAS mutational profiles, metabolic needs, and the tumor microenvironment to develop optimal treatment approaches.