The discovery of genetic alterations in the form of mainly genomic markers gave rise to a targeted therapy approach to medicine whereby mutations could be molecularly profiled and clinically actionable, becoming one of the foundations of precision oncology. The EGFR, RAF, KRAS, and BRAF mutations were part of the signaling pathways that led to the development of inhibitors that block growth and proliferation in cancer cells. Most notably, the BRAFV600E inhibitors and KRASG12C inhibitors became the standard of care (SOC) for melanoma and non–small cell lung cancer (NSCLC). Mutations such as the dMMR/MSI-H and NTRK fusions became the basis for the approval of tumor-agnostic therapies pembrolizumab and lactrectonib for NSCLC. Basket and umbrella trials are novel clinical study designs that have emerged. Pharmacogenomics is also playing a central role in precision oncology. Personalized medicine has led to a paradigm shift in oncology, leading to the novel discovery of molecular alterations, which has led to the development and implementation of personalized cancer medicines.