Recent advances in Next Generation Sequencing (NGS) have provided remarkable insights into the genomic characteristics of human cancers that have spurred a revolution in the field of oncology. The mitogen-activated protein kinase pathway (MAPK) and its activating cell receptor, the receptor tyrosine kinases (RTKs), which together encompass the (RTK)-RAS-RAF-MEK-ERK axis, are central to oncogenesis. A pan-cancer genomics analysis presented in this review is made possible by large collaborative projects, including The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and others. Landmark studies contributing to these projects have revealed alterations in cell signaling cascades that vary between cancer types and within tumors themselves. We review several of these studies in major tumor types to highlight recent advances in our understanding of the role of (RTK)-RAS-RAF alterations in cancer. Further studies are needed to increase the statistical power to detect clinically relevant low-frequency mutations, in addition to the known (RTK)-RAS-RAF pathway alterations, and to refine the resolution of the genomic landscape that defines these cancer mutations. The (RTK)-RAS-RAF-MEK-ERK mutation status, and their prognostic value, are also examined and correlated with clinical phenotypes. Treatments targeting various components of this pathway are ongoing, and are often effective initially in defined subgroups of patients. However, resistance to these agents can develop through adaptive mechanisms. With our steady increase in understanding the molecular biology of cancer, ongoing evaluation and monitoring through genomic analysis will continue to provide important information to the clinician in the context of treatment selection, response, resistance and outcomes.