The article provides an overview of the current state and future directions of KRAS targeting therapies. KRAS, a key component of the RAS signaling pathway, is a major driver of oncogenesis in human cancers. Despite its structural challenges, recent advancements in bioengineering and organic chemistry have enabled the development of direct KRAS inhibitors. The success of allele-specific targeting of KRAS G12C in non-small cell lung cancer (NSCLC) has led to the regulatory approval of sotorasib and adagrasib. These inhibitors have shown promising clinical efficacy, particularly in NSCLC and colorectal cancer (CRC). However, challenges remain, including the development of resistance mechanisms such as genetic mutations and adaptive feedback loops. The article discusses various strategies to overcome resistance, including combination therapies with receptor tyrosine kinases (RTKs), SOS1/SHP2 inhibitors, and downstream MAPK blockades. It also explores emerging approaches such as proteolysis targeting chimeric (PROTAC) technology and immunotherapeutic strategies. The future of KRAS therapeutics is expected to be highly impactful, with ongoing clinical trials evaluating combination therapies and novel drug classes. The article emphasizes the need for rigorous clinical evaluation and the potential of ctDNA monitoring to identify resistance mechanisms and guide treatment decisions.The article provides an overview of the current state and future directions of KRAS targeting therapies. KRAS, a key component of the RAS signaling pathway, is a major driver of oncogenesis in human cancers. Despite its structural challenges, recent advancements in bioengineering and organic chemistry have enabled the development of direct KRAS inhibitors. The success of allele-specific targeting of KRAS G12C in non-small cell lung cancer (NSCLC) has led to the regulatory approval of sotorasib and adagrasib. These inhibitors have shown promising clinical efficacy, particularly in NSCLC and colorectal cancer (CRC). However, challenges remain, including the development of resistance mechanisms such as genetic mutations and adaptive feedback loops. The article discusses various strategies to overcome resistance, including combination therapies with receptor tyrosine kinases (RTKs), SOS1/SHP2 inhibitors, and downstream MAPK blockades. It also explores emerging approaches such as proteolysis targeting chimeric (PROTAC) technology and immunotherapeutic strategies. The future of KRAS therapeutics is expected to be highly impactful, with ongoing clinical trials evaluating combination therapies and novel drug classes. The article emphasizes the need for rigorous clinical evaluation and the potential of ctDNA monitoring to identify resistance mechanisms and guide treatment decisions.