The need for precision therapies arises from the complexities associated with high-risk types of cancer, due to their aggressiveness and resistance to treatment. These diseases represent a global issue that requires transversal strategies involving cooperation among oncology specialists and experts from related fields, including nanomedicine. Nanoparticle-mediated active targeting of tumors has proven to be a revolutionary approach to address the most challenging neoplasms by overcoming the poor permeation at tumor site of untargeted, and nowadays questioned, strategies that rely solely on Enhanced Permeability and Retention (EPR) effects. The decoration of nanoparticles with Arg-Gly-Asp (RGD) peptides, which selectively target integrins on the cell membrane, marks a turning point in tumor microenvironment (TME) targeted strategies, enabling precision and efficiency in the delivery of chemotherapeutics. This review delves into the intricacies of the TME's features and targetable components (i.e. integrins), and the development of RGDs for nanoparticles' functionalization for active TME targeting. It provides a translational perspective on the integration of RGD-functionalized nanoparticles in oncology, highlighting their potential to overcome current therapeutic challenges, particularly in precision medicine. The current landscape of targeted nanomedicines in the clinic, and the development of RGD-nanomedicine for pediatric cancers are also discussed.