The diffusion of high-throughput next-generation sequencing technologies has sustained massive parallel sequencing of tumor tissue providing a deep insight into tumor biology and advancement of personalized medicine. A substantial number of targeted agents have been investigated in gynecologic cancer and some have received U.S. Food and Drug Administration approval, like PARP inhibitors in ovarian cancer, bevacizumab in ovarian and cervical cancers, and pembrolizumab in microsatellite-unstable or mismatch repair-deficient endometrial cancer. To improve effectiveness of targeted therapy, identification of predictive biomarkers able to guide the selection of the correct drug for the correct patient is crucial. Different limitations must be addressed to favor a more rapid implementation of a genotyping approach in treatment selection, such as the possibility to easily assess tumor heterogeneity and clonal evolution along the disease trajectory and the need for innovative trial designs like adaptive or basket trials incorporating molecular features as selection criteria. A deep dive into the genomic features of exceptional responders may also favor better understanding of tumor biology, mechanism of action of a specific target agent, and identification or predictive biomarkers for subsequent tailored studies.