Working on an understudied disease, bladder cancer, Theodorescu’s pioneering convergence of cell, computational, and translational biology led to the discovery of genes that regulate tumor growth, metastasis, and therapeutic response. He translated these findings into prognostic and predictive biomarkers and targets for small molecule therapeutics. His most significant scientific accomplishment is the discovery that loss of the Y chromosome in tumors drives growth and poor patient outcomes by giving tumors the ability to evade the immune system. However, this advantage comes with the liability of being more sensitive to immune checkpoint inhibitors providing both a novel stratification concept and platform for future therapy improvements for patients. Most recently, he applied Artificial Intelligence on muti-omic data to develop the concept of the “Molecular Twin”, a novel precision oncology approach that shows promise in discovering novel targets for therapy and parsimonious biomarkers of response that are superior to currently used ones. The variety and parsimonious nature of the marker panels has potential to help democratize precision medicine globally. He conceptualized the approach and led the discovery of a “first in class” RalGTPase inhibitor as a new therapeutic in human cancer that has been awarded US and international patents and is in commercial development. Using in vivo functional genomics, he identified targets such as DDR2 that when inhibited with small molecules increase the effectiveness of immune checkpoint inhibitors laying a rational foundation of novel combination therapies. He was also the first to characterize bladder cancer heterogeneity using single cell technology and, in this process, identified a new population of cancer cells whose presence in human tumors predicts poor outcome after both surgery and immune checkpoint inhibitors. This study will likely change the current approach to bladder cancer subtyping. He is the founding co-editor in chief of Bladder Cancer, the first journal focused on this disease and an elected member of the Association of American Physicians (AAP), the American Association of Genitourinary Surgeons (AAGUS), the American Surgical Association (ASA) and the National Academy of Medicine (NAM).