Population- and systems-based interventions need evaluation, but the randomized controlled trial (RCT) research design has significant limitations when applied to their complexity. After some years of being largely dismissed in the ranking of evidence in medicine, alternatives to the RCT have been debated recently in public health and related population and social service fields to identify the trade-offs in their use when randomization is impractical or unethical. This review summarizes recent debates and considers the pragmatic and economic issues associated with evaluating whole-population interventions while maintaining scientific validity and credibility.