Public concern over the environmental and public health impacts of the emerging contaminant class “microplastics” has recently prompted government agencies to consider mitigation efforts. Microplastics do not easily fit within traditional risk-based regulatory frameworks because their persistence and extreme diversity (of size, shape, and chemical properties associated with sorbed chemicals) result in high levels of uncertainty in hazard and exposure estimates. Due to these serious complexities, addressing microplastics’ impacts requires open collaboration between scientists, regulators, and policymakers. Here we describe ongoing international mitigation efforts, with California as a case study, and draw lessons from a similarly diverse and environmentally persistent class of emerging contaminants (per- and polyfluoroalkyl substances) that is already disrupting traditional regulatory paradigms, discuss strategies to address challenges associated with developing health-protective regulations and policies related to microplastics, and suggest ways to maximize impacts of research.