Organoids are self-organizing, expanding 3D cultures derived from stem cells. Using tissue derived from patients, these miniaturized models recapitulate various aspects of patient physiology and disease phenotypes, including genetic profiles and drug sensitivities. As such, patient-derived organoid (PDO) platforms provide an unprecedented opportunity for improving preclinical drug discovery, clinical trial validation, and, ultimately, patient care. Here, we review the evolution and scope of organoid technology, highlight recent encouraging results using PDOs as potential patient “avatars” to predict drug response and outcomes, and discuss critical parameters for widespread clinical adoption. These include improvements in assay speed, reproducibility, standardization, and automation, which are necessary to realize the translational potential of PDOs as clinical tools. The multiple entry points where PDOs may contribute valuable insights in drug discovery and lessen the risks associated with clinical trials are also discussed.