Interventional Oncology (IO) is emerging as the fourth pillar of cancer care alongside medical, radiation, and surgical oncology. Interventional oncologists provide minimally invasive image-guided therapies to treat cancers without the toxicities and disfigurement of chemotherapy, radiation or surgery. New clinical trial designs and collaborations are essential to determine how and when IO therapies should be integrated into multidisciplinary care plans to achieve optimal outcomes for cancer patients. Obstacles to this are many. Trial designs must accommodate staged and repeatable therapies, which complicates time-to-event analysis. There is a dearth of interventional oncology clinical investigators, who are needed to build collaborations with other oncologic disciplines to develop new concepts and protocols for clinical trials. The NCI cooperative group hierarchy is the domain of medical oncology. Surgical and interventional concepts struggle to hurdle the many layers of the review process, which is a barrier to the recruitment and retention of young investigators. Less than 5% of the >100 NCTN trials open at the applicant’s cancer center involve more than one cancer specialty, a stark indicator of the deficit in interdisciplinary clinical research. Conducting interdisciplinary trials is fraught with logistical and administrative challenges when the treating physicians practice in different departments, which historically is a major determinant of trial failure. The role of a senior IO clinical research specialist is to address each of these obstacles at the institutional and NCTN level. This starts with teaching clinical trial design and execution to a new cadre of young investigators from all cancer disciplines. Interdisciplinary collaborations can then be created within and across NCTN institutions to generate new trial concepts investigating the intersection of systemic and image-guided therapies to create new therapeutic synergies. Areas ripe for investigation include potentiation of ischemia by targeting HIF activation, autophagy, and free radical generation; potentiation of selective internal radiation with radiosensitizers; potentiation of thermal-based therapies to improve ablation margins; ablation and embolization as immunostimulants to potentiate immune checkpoint inhibition; image-guided delivery of CAR-T cells into solid tumors; direct injection and intralymphatic administration of vaccine-based agents; and nanoconstructs for delivery of therapeutic agents. These novel concepts need to be guided through the labyrinthian NCTN process, and new platforms developed for execution of interdepartmental clinical trials.