Unhealthy lifestyle behaviors such as poor diets and physical inactivity account for most of the cardiometabolic disease (CMD) burden, including type 2 diabetes and cardiovascular diseases. Much of this burden is mediated by the effects of unhealthy lifestyle behaviors on overweight and obesity, and disproportionally impacts certain population groups-including those from disadvantaged socioeconomic backgrounds. Combined lifestyle interventions (CLIs), which target multiple behaviors, have the potential to prevent CMD, but their implementation, reach and effectiveness in routine practice are often limited. Considering the increasing availability of effective but expensive pharmaceutical options for weight loss, we review the short-term and long-term benefits and cost-effectiveness of CLIs on overweight, obesity and associated CMDs, in controlled studies and in routine care. Against the backdrop of changing living environments, we discuss the effective components of CLIs and the many challenges associated with implementing them. Finally, we outline future directions for research and implications for policy and practice to improve lifestyle behaviors and cardiometabolic health at the population level.