The article reviews the current evidence and challenges in KRAS G12C inhibitor combination therapies. KRAS, a key oncogene, is frequently altered in various cancers, including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). Despite the high prevalence of KRAS alterations, targeting KRAS has been challenging due to its inaccessible binding surface and high affinity to guanosine nucleotides. The discovery of KRAS G12C inhibitors, such as sotorasib and adagrasib, has shown promise in monotherapy for NSCLC, with FDA approval for KRAS G12C-mutated advanced NSCLC. However, monotherapy has not demonstrated sufficient efficacy for other indications like CRC or PDAC, leading to the exploration of combination therapies. The article discusses the mechanisms of primary and acquired resistance to KRAS G12C inhibitors, including collateral signaling and genomic co-alterations. It reviews clinical trials combining KRAS G12C inhibitors with other targeted therapies, such as receptor tyrosine kinase (RTK) inhibitors (e.g., cetuximab, panitumumab), SHP2 inhibitors, MEK inhibitors, immunotherapies, and chemotherapy. These combinations aim to enhance efficacy by targeting multiple oncogenic pathways. Preclinical evidence suggests potential benefits from combining KRAS G12C inhibitors with other therapeutic targets, such as SOS1, wild-type RAS, ERK, PI3K, mTOR, CDK4/6, AURKA, ULK1/2, PARP, CXCR1/2, and VEGF. The article also highlights ongoing clinical trials investigating these combinations. The conclusion emphasizes the ongoing expansion of research into non-G12C mutations of KRAS and the potential for potent KRAS inhibitors and rational combinations to transform the treatment landscape for KRAS-mutated malignancies.The article reviews the current evidence and challenges in KRAS G12C inhibitor combination therapies. KRAS, a key oncogene, is frequently altered in various cancers, including colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic ductal adenocarcinoma (PDAC). Despite the high prevalence of KRAS alterations, targeting KRAS has been challenging due to its inaccessible binding surface and high affinity to guanosine nucleotides. The discovery of KRAS G12C inhibitors, such as sotorasib and adagrasib, has shown promise in monotherapy for NSCLC, with FDA approval for KRAS G12C-mutated advanced NSCLC. However, monotherapy has not demonstrated sufficient efficacy for other indications like CRC or PDAC, leading to the exploration of combination therapies. The article discusses the mechanisms of primary and acquired resistance to KRAS G12C inhibitors, including collateral signaling and genomic co-alterations. It reviews clinical trials combining KRAS G12C inhibitors with other targeted therapies, such as receptor tyrosine kinase (RTK) inhibitors (e.g., cetuximab, panitumumab), SHP2 inhibitors, MEK inhibitors, immunotherapies, and chemotherapy. These combinations aim to enhance efficacy by targeting multiple oncogenic pathways. Preclinical evidence suggests potential benefits from combining KRAS G12C inhibitors with other therapeutic targets, such as SOS1, wild-type RAS, ERK, PI3K, mTOR, CDK4/6, AURKA, ULK1/2, PARP, CXCR1/2, and VEGF. The article also highlights ongoing clinical trials investigating these combinations. The conclusion emphasizes the ongoing expansion of research into non-G12C mutations of KRAS and the potential for potent KRAS inhibitors and rational combinations to transform the treatment landscape for KRAS-mutated malignancies.