Molecularly derived profiles obtained from solid tumors have given rise to the development and implementation of targeted therapies, due in part to advancements in next-generation sequencing (NGS) and basic, clinical, and translational research into small molecule inhibitors and biologics. The tumor types highlighted are breast cancer, lung cancer, melanoma, and colorectal cancer, tumors for which targeted therapies have entered into first- and second-line stages in treatment. The focus is on oncogenic transformation as the primary driver of cancer and tumor suppressor genetic targets. Recent clinical studies into novel treatments and biomarkers are elaborated on, including homologous recombination deficiency in prostate and ovarian cancer and the extensively studied KRAS target. Mechanisms of action for targets and their signaling pathways and mechanism resistance are also discussed. New investigational agents resulting from preclinical models and tumor-agnostic therapies evaluated from early-stage clinical studies are described.