Malignancies heterogeneity represents a critical issue in cancer care, as it often causes therapy resistance and tumor relapse. Organoids are three-dimensional (3D) miniaturized representations of selected tissues within a dish. Lately, organoid technology has been applied to oncology with growing success and Patients Derived Tumor Organoids (PDTOs) constitute a novel available tool which fastens cancer research. PDTOs are in vitro models of cancer, and importantly, they can be used as a platform to validate the efficacy of anti-cancer drugs. For that reason, they are currently utilized in clinics as emerging in vitro screening technology to tailor the therapy around the patient, with the final goal of beating cancer resistance and recurrence. In this sense, PDTOs biobanking is widely used and PDTO-libraries are helping the discovery of novel anticancer molecules. Moreover, they represent a good model to screen and validate compounds employed for other pathologies as off-label drugs potentially repurposed for the treatment of tumors. This will open up novel avenues of care thus ameliorating the life expectancy of cancer patients. This review discusses the present advancements in organoids research applied to oncology, with special attention to PDTOs and their translational potential, especially for anti-cancer drug testing, including off-label molecules.