Invasive species are a leading driver of global change, with consequences for biodiversity and society. Because of extraordinary rates of endemism, introduction, and extinction, Hawaii offers a rich platform for exploring the cross-disciplinary challenges of managing invasive species in a dynamic world. We highlight key successes and shortcomings to share lessons learned and inspire innovation and action in and beyond the archipelago. We then discuss thematic challenges and opportunities of broad relevance to invaded ecosystems and human communities. Important research needs and possible actions include eradicating mammals from “mainland island” sanctuaries, assessing hidden threats from poorly known introduced species, harnessing genomic tools to eradicate disease vectors, structured decision making to achieve common objectives among diverse stakeholders, and enhancing capacity through nontraditional funding streams and progressive legislation. By shining a spotlight on invasive species at the front lines in Hawaii, we hope to catalyze strategic research and practice to help inform scientists and policymakers.