The theme of this commentary is to discuss the need for, and challenges of, conceptualizing, implementing, and evaluating multilevel health behavior change interventions. Ecological models, recommendations from national and international authoritative groups, and growing evidence all support the need for interventions designed to change multiple levels of influence, including individuals, social environments, organizations, built environments, and policies, to achieve population improvements in public health. Though multilevel interventions are becoming more common in practice, they are still under-used, and research on multilevel interventions is relatively rare. Drawing on examples from physical activity, several types of evidence are summarized to demonstrate that multilevel interventions are feasible and can be effective. Serious challenges to implementing and evaluating multilevel interventions include the need for teams with diverse expertise, lack of control over intervention implementation, unpredictability of timelines, managing complex teams over extended periods, and need to apply unfamiliar and less-rigorous study designs and methods. Recommendations are offered for changes in training, funding priorities, and academic incentives that could lead to more and better multilevel interventions.