There is strong interest in implementation science to address the gap between research and practice in public health. Research on the sustainability of evidence-based interventions has been growing rapidly. Sustainability has been defined as the continued use of program components at sufficient intensity for the sustained achievement of desirable program goals and population outcomes. This understudied area has been identified as one of the most significant translational research problems. Adding to this challenge is uncertainty regarding the extent to which intervention adaptation and evolution are necessary to address the needs of populations that differ from those in which interventions were originally tested or implemented. This review critically examines and discusses conceptual and methodological issues in studying sustainability, summarizes the multilevel factors that have been found to influence the sustainability of interventions in a range of public health and health care settings, and highlights key areas for future research.