RAS is frequently mutated in cancer, and RAS oncogenes have been reported in almost 30% of all malignant tumors. Mutated RAS isoforms (KRAS/NRAS/HRAS) are most commonly found in solid tumors, including pancreatic, colorectal and lung adenocarcinomas, as well as melanoma, making RAS a highly attractive target for a novel anti-cancer drug. Oncogenic mutations promote RAS to occur mainly in the GTP-bound active state, due to diminished intrinsic GTPase activity, insensitivity to GTPase activating protein (GAPs) and/or elevated nucleotide exchange. These changes are associated with tumorigenesis as a result of the constantly active RAS signaling pathways, promoting uncontrolled cell division and epithelial invasion. More than 85% of HRAS and 95% of both KRAS and NRAS mutations occur at the so called ''hotspot'' codons, G12, G13 and Q61. In the case of non-small cell lung cancer (NSCLC), KRAS(G12C) is found in ~ 40% of all cases. RAS was found to be a difficult drug target, and before the success with the covalent G12C inhibitors, it was even considered "undruggable". Covalent inhibitors offer prolonged target engagement, an advantage they have already demonstrated in clinical trials, also in the context of KRAS(G12C). Two covalent KRAS(G12C) inhibitors engaging the cryptic switch-II pocket (SII-P), sotorasib (AMG-510; Lumakras ® /Lumykras ® ) and adagrasib (MRTX849; Krazati ® ), have recently been approved by FDA and EMA for the treatment of non-small cell lung cancer (NSCLC). Both inhibitors target the GDP-bound state of KRAS(G12C), trapping the protein in this inactive state, thus inhibiting the overactive KRAS downstream signaling. Successful targeting of KRAS(G12C) with this type of compounds does not only rely on the unique cysteine, which enables the covalent bond formation, but also on the intrinsic GTPase activity of KRAS(G12C). The SII-P is easier accessible and/or sampled more frequently when KRAS is GDP-bound, and this feature promotes targeting KRAS(G12C). However, at the same time it can be considered rather unsuitable for some other oncogenic KRAS alleles (e.g. G12R and Q61R) that are almost exclusively GTP-bound in cells. Most recently, covalent targeting of the KRAS SII-P was demonstrated viable also for its GTP-bound state for the KRAS(G12C) and G12D. The cryptic SII-P has been extensively probed due to its dynamic nature, originating from the highly flexible switch-II region. Many peptides and small molecule ligands have been designed to exploit this cryptic pocket for binding to RAS. Early covalent inhibitors such as ARS-1620 targeted this pocket, however, with significantly compromised binding properties in comparison to the clinically approved sotorasib and adagrasib. Both inhibitors have demonstrated clinical efficacy as monotherapy and are currently being evaluated in combination with other treatment modalities. Recently, resistance and reactivation of the RAS pathways after inhibitor treatment have been reported to occur via both on-target and off-target mechanisms. The on-target mechanisms include alterations in the KRAS(G12C) SII-P composition. While clinical and preclinical data emerge, detailed information on the (noncovalent) binding specificities and interactions of these compounds towards other RAS proteins is unfortunately rather incomplete. Only recently, SII-P engagement by noncovalent ligands was systematically studied for the first time using sotorasib and adagrasib as model compounds. In this context, Shokat et al. highlighted the accessibility of the SII-P for noncovalent ligands in various KRAS mutants beyond G12C. Among the noncovalent inhibitors, MRTX1133, which targets G12D mutations, has already entered clinical trials. In this study, we elucidate the detailed binding mechanism of sotorasib and adagrasib, as well as the mechanism by which resistance arises through mutations at residues H95 and Y96. Using an ultra-sensitive thermal stability assay (TSA) and nucleotide exchange assays with HRAS, NRAS, and multiple KRAS mutants including H95L and Y96D mutations, we demonstrate distinct specificity profiles for sotorasib and adagrasib. Cell-based assays and molecular dynamics (MD) simulations support these biochemical results, providing atomiclevel insights into the non-covalent binding specificities of these inhibitors. Additionally, the results suggest a previously unidentified resistance mechanism of Y96D. Both the biochemical and the computational data reveal the irreplaceable nature of H95 and Y96 for interactions with sotorasib and adagrasib. Furthermore, we demonstrate potential mechanisms for direct target engagement of non-G12C oncogenic KRAS mutants via the SII-P and for achieving KRAS specificity over NRAS and HRAS by exploiting interactions at residue H95. The data also reveales that, while adagrasib is KRAS specific, sotorasib can effectively target not only KRAS(G12C), but also the G12C mutants of NRAS and HRAS, potentially offering new treatment possibilities for cancer patients harboring these rarer genetic alterations.