Research, especially clinical trials, during outbreaks often poses enormous challenges, and up until very recent times was often considered almost impossible. However, for diseases such as Ebola virus disease, which are seen almost exclusively in outbreak form, outbreaks are the only opportunity to perform studies and accrue knowledge. Here, we discuss our experiences and lessons learned implementing a clinical study of an Ebola virus vaccine during an outbreak of that disease in 2018–20 in eastern Democratic Republic of the Congo. Keys to success is these settings include forging partnerships with diverse and complementary experience and skills, working out clear roles and responsibilities, communicating and engaging with the community as an essential partner, and maintaining flexibility to adapt to unexpected events. Progress in these complex settings requires both quick action to implement studies as soon as possible, coupled with patience, realizing that results often come with a sequential long-term approach across outbreaks as opportunities arise. Despite the many challenges, where the political will is there and the right team assembled, significant progress can be made, contributing both to control of the present outbreak and prevention or enhanced control of the next one.