KRAS G12C inhibitors have shown promise in targeting KRAS mutations, but monotherapy has limited efficacy due to primary and acquired resistance. Combining KRAS G12C inhibitors with other therapies, such as RTK, SHP2, and MEK inhibitors, has shown promising results, especially in KRAS G12C-mutated colorectal cancer. Ongoing trials are exploring combinations with SOS1, ERK, CDK4/6, and wild-type RAS. Preclinical data suggest additional potential combinations with YAP/TAZ-TEAD, FAK, and farnesyltransferase inhibitors. Combinations with immunotherapy and chemotherapy are also being investigated. New KRAS-targeted therapies beyond G12C are being developed, potentially broadening treatment options. Rational combination of KRAS inhibitors with other therapies is likely to play a significant role in future treatment for KRAS-mutated solid tumors. Current evidence highlights the importance of targeting multiple pathways to overcome resistance and improve outcomes. Ongoing clinical trials are evaluating various combinations, including with RTK inhibitors, SHP2 inhibitors, MEK inhibitors, immunotherapy, and chemotherapy. Preclinical studies suggest additional potential targets, and research continues to explore new combinations and mechanisms to enhance the efficacy of KRAS G12C inhibitors.KRAS G12C inhibitors have shown promise in targeting KRAS mutations, but monotherapy has limited efficacy due to primary and acquired resistance. Combining KRAS G12C inhibitors with other therapies, such as RTK, SHP2, and MEK inhibitors, has shown promising results, especially in KRAS G12C-mutated colorectal cancer. Ongoing trials are exploring combinations with SOS1, ERK, CDK4/6, and wild-type RAS. Preclinical data suggest additional potential combinations with YAP/TAZ-TEAD, FAK, and farnesyltransferase inhibitors. Combinations with immunotherapy and chemotherapy are also being investigated. New KRAS-targeted therapies beyond G12C are being developed, potentially broadening treatment options. Rational combination of KRAS inhibitors with other therapies is likely to play a significant role in future treatment for KRAS-mutated solid tumors. Current evidence highlights the importance of targeting multiple pathways to overcome resistance and improve outcomes. Ongoing clinical trials are evaluating various combinations, including with RTK inhibitors, SHP2 inhibitors, MEK inhibitors, immunotherapy, and chemotherapy. Preclinical studies suggest additional potential targets, and research continues to explore new combinations and mechanisms to enhance the efficacy of KRAS G12C inhibitors.