Despite the discovery of oncogenes in human tumor DNA 40 years ago, the development of effective targeted therapies directed against has lagged behind those more successful advancements in the field of therapeutic tyrosine kinase inhibitors targeting other oncogenes such as , , and . The discoveries that (1) malignant oncogenes differ from their wild-type counterparts by only a single amino acid change and (2) covalent inhibition of the cysteine residue at codon 12 of in its inactive GDP-bound state resulted in effective inhibition of oncogenic RAS signaling and have catalyzed a dramatic shift in mindset toward -driven cancers. Although the development of allele-selective KRAS inhibitors has changed a treatment paradigm, the clinical activity of these agents is more modest than tyrosine kinase inhibitors targeting other oncogene-driven cancers. Heterogeneous resistance mechanisms generally result in the restoration of RAS/mitogen-activated protein kinase pathway signaling. Many approaches are being evaluated to overcome this resistance, with many combinatorial clinical trials ongoing. Furthermore, because and are more prevalent than , there remains an unmet need for additional therapeutic strategies for these patients. Thus, our current translational standing could be described as "the end of the beginning," with additional discovery and research innovation needed to address the enormous disease burden imposed by -mutant cancers. Here, we describe the development of KRAS inhibitors, the challenges of resistance to these inhibitors, strategies to mitigate that resistance, and new approaches being taken to address other -mutant cancers.